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

squamous cell Epithelium or epithelial tissue is one of the four basic types of animal tissue, along with connective tissue, muscle tissue and nervous tissue. It is a thin, continuous, protective layer of compactly packed cells with a little intercellula ...

epithelial Epithelium or epithelial tissue is one of the four basic types of animal tissue, along with connective tissue, muscle tissue and nervous tissue. It is a thin, continuous, protective layer of compactly packed cells with a little intercellula ...

cancer Cancer is a group of diseases involving abnormal cell growth with the potential to invade or spread to other parts of the body. These contrast with benign tumors, which do not spread. Possible signs and symptoms include a lump, abnormal b ...

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, duplica ...

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, I ...

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 102 million base pairs (the building material of DNA) and represents between 3% and 3.5% of the total DN ...

is fused to '' BRD4'' 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 Who or WHO may refer to: * Who (pronoun), an interrogative or relative pronoun * Who?, one of the Five Ws in journalism * World Health Organization Arts and entertainment Fictional characters * Who, a creature in the Dr. Seuss book '' Horton He ...

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

Signs and symptoms

In the United States, about 20–30 cases are reported each year. This may be a gross underestimate of the total number of cases as few laboratories have the reagents and expertise to make the diagnosis. 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) 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 animals may ...

neck The neck is the part of the body on many vertebrates that connects the head with the torso. The neck supports the weight of the head and protects the nerves that carry sensory and motor information from the brain down to the rest of the body. In ...

and

mediastinum The mediastinum (from ) is the central compartment of the thoracic cavity. Surrounded by loose connective tissue, it is an undelineated region that contains a group of structures within the thorax, namely the heart and its vessels, the esophagu ...

. 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 epit ...

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 descri ...

immunohistochemistry Immunohistochemistry (IHC) is the most common application of immunostaining. It involves the process of selectively identifying antigens (proteins) in cells of a tissue section by exploiting the principle of antibodies binding specifically to an ...

. However, the defining feature of NCs is rearrangement of the ''NUT'' gene. Most common is a translocation involving the BRD4 gene and

NUT gene Nut often refers to: * Nut (fruit), fruit composed of a hard shell and a seed, or a collective noun for dry and edible fruits or seeds * Nut (hardware), fastener used with a bolt Nut or Nuts may also refer to: Arts, entertainment, and media Co ...

(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 BET protein, Bromodomain and Extra-Terminal motif (BET) proteins BRD2, BRD3, BRD4, and BRDT, and prevent protein-protein interaction between BET proteins and acetylated hi ...

and

histone deacetylase inhibitor Histone deacetylase inhibitors (HDAC inhibitors, HDACi, HDIs) are chemical compounds that inhibit histone deacetylases. HDIs have a long history of use in psychiatry and neurology as mood stabilizers and anti-epileptics. More recently they are bei ...

s (HDACi)) may help to yield growth arrest of the neoplastic cells.

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