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Basic Facts about NUT Midline Carcinoma





Registry Personnel


As a genetically defined cancer, NMC cannot be diagnosed by morphology alone. The diagnosis of NUT midline carcinoma is made definitively by demonstration of NUT rearrangement by fluorescent in situ hybridization (FISH) or by demonstration of a BRD4-NUT fusion transcript by RT-PCR. FISH is preferred because it will detect all NMCs, including all NUT-variants, whereas RT-PCR can currently only detect BRD3- or BRD4-NUT tumors. Fortunately, the screening for NMC has just been made vastly easier with the availability of a commercial antibody against NUT from Cell Signaling Technologies, Inc. (CST, Danvers, MA). We developed this monoclonal rabbit antibody in collaboration with CST for the purpose of diagnosing NMC by immunohistochemistry (IHC), based on the knowledge that NUT expression should not be seen normally outside the testis. IHC with the NUT antibody demonstrates speckled nuclear staining in nearly all NMC tumor cells (Fig. 1), except for within differentiated cells, whereas no staining is seen in non-NMC cancers, with the exception of faint staining of germ cell tumor nuclei, and hepatocytes. Our findings were that the antibody has an 87% sensitivity, and 100% specificity (Haack H, et al., 2009), thus strongly positive staining is virtually diagnostic of NMC.

Figure 1. Diagnosis of NUT midline carcinoma using a monoclonal antibody to NUT. Left, typical absence of staining of a non-NMC, in this case a sinonasal undifferentiated carcinoma. By contrast, right, known NMCs reveal diffuse (>90%), speckled, nuclear staining. Below, table demonstrating accuracy of C52 antibody in diagnosis of NMC.

The challenge is no longer the diagnosis of NMC, but to determine when to perform the test, the reagents for which, though commercially available, are not widely available in pathology laboratories. If NMC is not to be missed, any poorly differentiated, monomorphic, midline neoplasm that does not stain for lineage-specific markers should be considered for NUT-rearrangement testing. This group includes sinonasal undifferentiated carcinomas (SNUC) and any poorly differentiated carcinoma, with or without squamous differentiation, whose cells lack the pronounced atypia and pleomorphism characteristic of garden variety poorly differentiated carcinomas. Also included in the differential diagnosis are undifferentiated malignant tumors, such as small round blue cell tumors. Amongst this group are Ewing sarcoma and acute leukemia, both of which have been closely mimicked by NMC, resulting in misdiagnosis (Fig. 2). Squamous differentiation, evidence morphologically or by positive p63 IHC, is common in NMCs, and may occasionally be extensive. A curious, characteristic finding is focal abrupt squamous differentiation, where stratification and gradual differentiation are absent, resembling Hassel’s corpuscles. To our knowledge, abrupt squamous differentiation, while common in NMCs, is rarely seen in other carcinomas.

Figure 2. NMCs are monomorphic, poorly differentiated carcinomas with varying degrees of squamous differentiation. (A-B) NMCs can mimic other undifferentiated neoplasms such as germ cell tumors, Ewing’s sarcoma, or lymphoma. (C-D) Abrupt squamous differentiation is characteristic of some NMCs. (E-F) NUT-variant NMCs look similar to BRD4-NUT tumors. (G) Rarely, there can be extensive squamous differentiation. (H-I) Poorly differentiated, non-NMC carcinomas often display pleomorphism and atypia that is uncharacteristic of NMCs.

Tumor Monomorphic Distinguishing marker* Abrupt squamous cell differentiation
Basaloid SQC - HPV 20-22 -
Ewings/PNET +   -
Extra-Gonadal Germ Cell Tumor + PLAP, Oct 3/4, -HCG -
Lymphoma/Leukemia + LCA -
Nasopharyngeal Carcinoma + EBV -
HPV-related squamous cell carcinoma +/- HPV +
Non-NMC PDSQC -   -
Olfactory Neuroblastoma + Synaptophysin -
PD carcinoma -   -
Small Cell Carcinoma +   -
SNUC +   -

Pathology Consultation

Consultation to review/confirm the diagnosis of NUT midline carcinoma is provided by the Registry pathologist. If the diagnosis has already been made by the above criteria, confirmation by central review is free-of-charge. If not, then review will subject to regular consultation billing by the Brigham and Women’s Hospital Dept. of Pathology. This process also fulfills central review if the patient is eventually enrolled in the Registry.

In addition to diagnostic assistance and Registry enrollment, the Registry asks pathologists to consider sending tissue to the NMC Registry Tissue Bank. For details, click HERE.

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