NUT carcinoma (NC; formerly NUT midline carcinoma (NMC)) is a rare genetically defined, very aggressive

squamous cell Epithelium or epithelial tissue is a thin, continuous, protective layer of Cell (biology), cells with little extracellular matrix. An example is the epidermis, the outermost layer of the skin. Epithelial (Mesothelium, mesothelial) tissues line ...

epithelial Epithelium or epithelial tissue is a thin, continuous, protective layer of cells with little extracellular matrix. An example is the epidermis, the outermost layer of the skin. Epithelial ( mesothelial) tissues line the outer surfaces of man ...

cancer Cancer is a group of diseases involving Cell growth#Disorders, abnormal cell growth with the potential to Invasion (cancer), invade or Metastasis, spread to other parts of the body. These contrast with benign tumors, which do not spread. Po ...

that usually arises in the midline of the body and is characterized by a

chromosomal rearrangement In genetics, a chromosomal rearrangement is a mutation that is a type of chromosome abnormality involving a change in the structure of the native chromosome. Such changes may involve several different classes of events, like deletions, duplicati ...

in the nuclear protein in testis gene (i.e. ''NUTM1'' gene). In approximately 75% of cases, the coding sequence of ''NUTM1'' in

band Band or BAND may refer to: Places *Bánd, a village in Hungary * Band, Iran, a village in Urmia County, West Azerbaijan Province, Iran * Band, Mureș, a commune in Romania * Band-e Majid Khan, a village in Bukan County, West Azerbaijan Province, ...

14 on the long (or "q") arm of

chromosome 15 Chromosome 15 is one of the 23 pairs of chromosomes in humans. People normally have two copies of this chromosome. Chromosome 15 spans about 99.7 million base pairs (the building material of DNA) and represents between 3% and 3.5% of the total DNA ...

is fused to ''

BRD4 Bromodomain-containing protein 4 is a protein that in humans is encoded by the ''BRD4'' gene. BRD4 is a member of the BET (bromodomain and extra terminal domain) family, which also includes BRD2, BRD3, and BRDT. BRD4, similar to other BET fam ...

'' or '' BRD3'', which creates a chimeric gene that encodes the ''BRD-NUT'' fusion protein. The remaining cases, the fusion of NUTM1 is to an unknown partner gene, usually called ''NUT''-variant. The name NUT carcinoma was introduced as the carcinoma does not only occur in the body midline; therefore,

WHO The World Health Organization (WHO) is a specialized agency of the United Nations which coordinates responses to international public health issues and emergencies. It is headquartered in Geneva, Switzerland, and has 6 regional offices and 15 ...

also changed the name in 2015 in the WHO Classification of Tumours of the Lung, Pleura, Thymus and Heart.

Signs and symptoms

The number of cases per year is likely grossly underestimated. One study suggests the incidence rate is likely around 1,000 cases per year in the United States. The symptoms are similar to other forms of cancer and dependent on the stage. While generalized symptoms (

weight loss Weight loss, in the context of medicine, health, or physical fitness, refers to a reduction of the total body mass, by a mean loss of fluid, body fat (adipose tissue), or lean mass (namely bone mineral deposits, muscle, tendon, and other conn ...

and

fatigue Fatigue is a state of tiredness (which is not sleepiness), exhaustion or loss of energy. It is a signs and symptoms, symptom of any of various diseases; it is not a disease in itself. Fatigue (in the medical sense) is sometimes associated wit ...

) may be seen, site specific symptoms are also present. If the tumor involves the head and neck region (in about 35%), then pain, a mass, obstructive symptoms, among others, may be experienced. NUT carcinomas are not specific to any tissue type or organ. Common sites include the

head A head is the part of an organism which usually includes the ears, brain, forehead, cheeks, chin, eyes, nose, and mouth, each of which aid in various sensory functions such as sight, hearing, smell, and taste. Some very simple ani ...

neck The neck is the part of the body in many vertebrates that connects the head to the torso. It supports the weight of the head and protects the nerves that transmit sensory and motor information between the brain and the rest of the body. Addition ...

and

mediastinum The mediastinum (from ;: mediastina) is the central compartment of the thoracic cavity. Surrounded by loose connective tissue, it is a region that contains vital organs and structures within the thorax, mainly the heart and its vessels, the eso ...

. The median age at diagnosis is 16–23 years, but older patients may be affected.

Diagnosis

NC when viewed microscopically, are poorly differentiated carcinomas which show abrupt transitions to islands of well-differentiated squamous epithelium. This tumor pattern is not specific or unique to NUT carcinoma, but this pattern is most suggestive of the diagnosis. The neoplastic cells will show a positive reaction with various

cytokeratin Cytokeratins are keratin proteins found in the intracytoplasmic cytoskeleton of epithelial tissue. They are an important component of intermediate filaments, which help cells resist mechanical stress. Expression of these cytokeratins within ep ...

s, p63, CEA, and

CD34 CD34 is a transmembrane phosphoglycoprotein protein encoded by the CD34 gene in humans, mice, rats and other species. CD34 derives its name from the cluster of differentiation protocol that identifies cell surface antigens. CD34 was first desc ...

immunohistochemistry Immunohistochemistry is a form of immunostaining. It involves the process of selectively identifying antigens in cells and tissue, by exploiting the principle of Antibody, antibodies binding specifically to antigens in biological tissues. Alber ...

. However, the defining feature of NCs is rearrangement of the ''NUT'' gene. Most common is a translocation involving the

gene and NUT gene (t(15;19)(q13;p13.1)). Therefore, staining with the NUT antibody confirms the diagnosis (although only available in a limited number of laboratories).

Differential diagnosis

The ''differential diagnosis'' is quite wide, but it is important to consider this tumor type when seeing a poorly differentiated tumor that shows abrupt areas of keratinization. Other tumors included in the differential diagnosis are sinonasal undifferentiated carcinomas, Ewing sarcoma/Primitive neuroectodermal tumor, leukemia, rhabdomyosarcoma, and melanoma. When NUT midline carcinoma is seen in the head and neck, the squamous lining of the cavities may be entrapped by the neoplastic cells, and so it is important to document the carcinoma cells in the rest of the tumor by a variety of stains (including cytokeratin or p63). One of the most helpful and characteristic findings is the focal abrupt squamous differentiation, where stratification and gradual differentiation are absent, resembling a Hassall corpuscle of the thymus.

Treatment

Currently, the standard treatment approach is a multimodal approach involving surgery as well as radio-chemotherapy. As the mean survival under this treatment regimen is only 5–7 months, more specific treatment options are under investigation: Specific molecular targeted therapies (including

BET inhibitors BET inhibitors are a class of drugs that reversibly bind the bromodomains of Bromodomain and Extra-Terminal motif (BET) proteins BRD2, BRD3, BRD4, and BRDT, and prevent protein-protein interaction between BET proteins and acetylated histones an ...

and

histone deacetylase inhibitor Histone deacetylase inhibitors (HDAC inhibitors, HDACi, HDIs) are chemical compounds that enzyme inhibitor, inhibit histone deacetylases. Since acetylation of histones, deacetylation of histones produces transcriptionally silenced heterochromatin ...

s (HDACi)) may help to yield growth arrest of the neoplastic cells. Two genetically engineered mouse models (GEMMs) of NC have been reported by the French lab (2023 ) and Gu lab (2024 ). These models demonstrate that BRD4-NUT alone drives malignant transformation and spread of NUT carcinoma and will help enable the discovery and development of novel, targeted therapies for NC.

Prognosis

NUT carcinoma is very resistant to standard chemotherapy treatments. The tumor may initially respond to therapy, and then rapid recurrence is experienced. A multimodality approach to treatment is advocated, especially since most patients present with advanced disease. Treatment must be tailored to the individual patient, with several promising new targeted molecular therapies in clinical trials. Overall, there is a mean survival of 6–9 months.

References

External links

Rare cancers {{DEFAULTSORT:NUT_carcinoma