IMMUNOHISTOCHEMISTRY STAINS:
FISH: positive for NUTM1 rearrangement
Chromosome shows ch15q inversion
Chromosome shows ch15q inversion
Diagnosis:
Metastatic NUT midline carcinoma.
NUT midline carcinoma (NMC) is a rare aggressive malignant epithelial tumor defined by rearrangements of the gene encoding nuclear protein of the testis (NUT) at 15q14.
The malignancies range from entirely undifferentiated carcinomas to carcinomas with prominent squamous differentiation. It originates from midline locations such as the head, neck or mediastinum. It occurs over a vast age range (Newborn-78 years), the median age at diagnosis is 17 years. There are 20-30 cases reported in USA.
Symptoms:
The symptoms are similar to other forms of cancer and dependent on the stage. While generalized symptoms (weight loss and fatigue) may be seen, site specific symptoms are also present. Most tumors have presented at advanced stage (lymph node metastases, bone metastases, pleural carcinomatosis).
Pathologic Findings:
Histologically, tumors are usually composed of sheets of undifferentiated cells. Occasional cases may have more nested malignant cells within a desmoplastic stroma. Large areas of coagulative necrosis may be present. The cells have scant amphiphilic or eosinophilic cytoplasm. Nuclei have irregular contours although they tend to be somewhat uniform in size. They have fine to vesicular chromatin and prominent nucleoli. Mitotic figures and apoptotic bodies are common. Squamous differentiation is frequently seen and does not necessarily predict the partner gene.
Immunohistochemistry:
Tumor cells react with antibodies to keratins (although staining may be focal), p63 (squamous differentiation). CD34 immunoreactivity was seen in a little more than half the cases. There is no immunoreactivity with other antigens expressed in small blue cells tumors of childhood such as CD45, desmin, myoglobin, smooth muscle actin, muscle actin, chromogranin, synaptophysin, leukocyte common antigen, placental alkaline phosphatase, S100 protein, alpha-fetoprotein, neuron specific enolase, CD57, and HMB45. Evidence of EBV and human papillomavirus (HPV) infection has not been identified. Immunoreactive to NUT protein is specific.
The definitive diagnosis of an NMC and the distinction of such a tumor based solely on histology and immunohistochemistry (excluding antibody to the NUT protein) is not considered possible
Cytogenetics:
The most common translocation is the t(15;19) (q14;p13.1), which fuses the NUT gene on chromosome 15 to the BRD4 gene. In about one-third of cases, however, the NUT gene is fused to a different partner gene (NUT-variant midline carcinoma). Rarely, the NUT gene is fused to the BRD3 gene at 9q34.2. The BRD proteins are known to bind transcriptionally active chromatin. The function of the NUT protein is not known, although it is only constitutively expressed in early germ cells and within the brain (ciliary ganglion). Some recent data suggest that the fusion proteins block epithelial and squamous differentiation.
Treatment and Prognosis
NUT midline carcinoma is very resistant to standard chemotherapy treatments. There is no established treatment for NMCs. The tumor may initially respond to therapy, and then rapid recur, followed by death. Most patients have received combination multi-drug chemotherapy and radiation. Only occasional cases have undergone subsequent resection. Of the patients with adequate follow-up in one series, all but one (15/16) have died of disease with an average survival time of 9 to 10 months.
Metastatic NUT midline carcinoma.
NUT midline carcinoma (NMC) is a rare aggressive malignant epithelial tumor defined by rearrangements of the gene encoding nuclear protein of the testis (NUT) at 15q14.
The malignancies range from entirely undifferentiated carcinomas to carcinomas with prominent squamous differentiation. It originates from midline locations such as the head, neck or mediastinum. It occurs over a vast age range (Newborn-78 years), the median age at diagnosis is 17 years. There are 20-30 cases reported in USA.
Symptoms:
The symptoms are similar to other forms of cancer and dependent on the stage. While generalized symptoms (weight loss and fatigue) may be seen, site specific symptoms are also present. Most tumors have presented at advanced stage (lymph node metastases, bone metastases, pleural carcinomatosis).
Pathologic Findings:
Histologically, tumors are usually composed of sheets of undifferentiated cells. Occasional cases may have more nested malignant cells within a desmoplastic stroma. Large areas of coagulative necrosis may be present. The cells have scant amphiphilic or eosinophilic cytoplasm. Nuclei have irregular contours although they tend to be somewhat uniform in size. They have fine to vesicular chromatin and prominent nucleoli. Mitotic figures and apoptotic bodies are common. Squamous differentiation is frequently seen and does not necessarily predict the partner gene.
Immunohistochemistry:
Tumor cells react with antibodies to keratins (although staining may be focal), p63 (squamous differentiation). CD34 immunoreactivity was seen in a little more than half the cases. There is no immunoreactivity with other antigens expressed in small blue cells tumors of childhood such as CD45, desmin, myoglobin, smooth muscle actin, muscle actin, chromogranin, synaptophysin, leukocyte common antigen, placental alkaline phosphatase, S100 protein, alpha-fetoprotein, neuron specific enolase, CD57, and HMB45. Evidence of EBV and human papillomavirus (HPV) infection has not been identified. Immunoreactive to NUT protein is specific.
The definitive diagnosis of an NMC and the distinction of such a tumor based solely on histology and immunohistochemistry (excluding antibody to the NUT protein) is not considered possible
Cytogenetics:
The most common translocation is the t(15;19) (q14;p13.1), which fuses the NUT gene on chromosome 15 to the BRD4 gene. In about one-third of cases, however, the NUT gene is fused to a different partner gene (NUT-variant midline carcinoma). Rarely, the NUT gene is fused to the BRD3 gene at 9q34.2. The BRD proteins are known to bind transcriptionally active chromatin. The function of the NUT protein is not known, although it is only constitutively expressed in early germ cells and within the brain (ciliary ganglion). Some recent data suggest that the fusion proteins block epithelial and squamous differentiation.
Treatment and Prognosis
NUT midline carcinoma is very resistant to standard chemotherapy treatments. There is no established treatment for NMCs. The tumor may initially respond to therapy, and then rapid recur, followed by death. Most patients have received combination multi-drug chemotherapy and radiation. Only occasional cases have undergone subsequent resection. Of the patients with adequate follow-up in one series, all but one (15/16) have died of disease with an average survival time of 9 to 10 months.