Teaching caseNSD3-NUT-expressing midline carcinoma of the lung: First characterization of primary cancer tissue
Introduction
Overall, malignant tumors of the lung that present with an undifferentiated morphology pose significant diagnostic challenges to attending surgical pathologists, especially in cases where a limited amount of biopsy material is available [20] and the immunohistochemical results are ambiguous or atypical [21]. Among these malignant neoplasms, nuclear protein in testis (NUT) midline carcinoma (NMC) is a recently recognized entity that is characterized by undifferentiated morphological features and immunoreactivity to NUT. This disease entity is notorious for its poor prognosis [1], [16].
NMCs of the lung have been reported, but they are extremely rare; only 5 cases, including 2 pediatric [20] and 3 adult [7], [21] cases, have been documented. Currently, the diagnosis of NMC depends on the identification of a genetic change (a rearrangement involving the NUT locus at 15q14) that generates a specific fusion transcript with a member of the bromodomain-containing protein (BRD) family, such as BRD4 located on chromosome 19p13.1. In approximately two-thirds of NMCs [6], [8], [9], BRD4-NUT is specifically detected. Less commonly, NMC can harbor a different rearrangement involving NUT [9]; that is, a subset (approximately 25%) of these cases exhibit a BRD3-NUT rearrangement. In the remaining cases, the genes involved in NUT rearrangement are unknown [9]. For example, fluorescence in situ hybridization (FISH) has demonstrated a BRD4-NUT rearrangement in 2 pediatric cases of NMC of the lung [20]. In the remaining 3 adult cases of NMC arising in the lung, although NUT rearrangements were suspected because of break-aparts of the NUT locus in the cancer cells, the partner gene, supposed to be fused with NUT, was not identified [7], [21]. To date, no “variant NMC” of the lung harboring a fusion other than BRD3/4-NUT has been reported.
Recently, a variant NMC cell line (1221) was established, for the first time, from the discarded lung tumor tissue of a poorly differentiated squamous cell carcinoma of the mediastinum that had metastasized to the lung [10]. Using this cell line, a novel NSD3 (nuclear receptor binding SET domain 3)-NUT fusion oncogene, which is both necessary and sufficient for the blockade of the differentiation and maintenance of proliferation in NMC cells, has been demonstrated [10]. Thus, NSD3 is a potential therapeutic target in NMC and a clinical example exhibiting this situation at a primary site has been sought.
In the present article, we describe the first case of an NSD3-NUT rearrangement identified in the primary tissue of an NMC of the lung; the NMC was diagnosed using immunohistochemistry with a highly sensitive and specific anti-NUT monoclonal antibody [11]. In addition, a NSD3-NUT fusion gene was successfully identified using 5′-rapid amplification of the cDNA end (RACE) and was validated using FISH.
Section snippets
Clinical summary
A 36-year-old woman sought medical advice because of a cough accompanied by wheezing with a 2-month duration. An enhanced computed tomography scan performed at the time of hospitalization revealed a tumor surrounding the proximal part of the left lower lobe bronchus with obstruction of the left bronchus B6 and extending to the middle mediastinum adjacent to the left hilum (Fig. 1), strongly indicating that the tumor was derived from the left lung rather than from the mediastinum. Metastatic
Histopathologic and immunohistochemical examination
The tissues were fixed in 10% buffered formalin and were embedded in paraffin after routine processing, followed by sectioning and staining with hematoxylin and eosin (H&E). Immunostaining was performed using DAKO autostainer universal staining system (DAKO, Glostrup, Denmark) with antibodies for the following antigens: CD5 (clone 4C7, 1:150 dilution, DAKO), CD30 (clone Ber-H2, 1:100, DAKO), CD45 (clone 2B11 + PD7/26, 1:150, DAKO), CD56 (clone CD564, 1:100, Leica Biosystems, Newcastle, United
Discussion
The histological features of tumors that have been reported as NMCs range from entirely undifferentiated carcinomas to carcinomas with prominent squamous differentiation [2], [3], [4], [8], [15]. Although abrupt keratinization had been assumed to be characteristic of NMC harboring a NUT gene rearrangement involving a gene other than BRD4 [7], it was not observed in our case, as well as in that with BRD4-NUT [19], [20]; thus, a diagnosis of NMC solely based on the morphology is difficult.
Conflicts of interest
The authors have no conflicts of interest to declare.
Acknowledgments
We appreciate the technical assistance of Ms. Kiyoko Nagura and Mr. Hisaki Igarashi of the Hamamatsu University School of Medicine and all the clinical and technical staff members of the Pathology Division of Iwata City Hospital.
This contribution was supported, in part, by Grants-in-Aid for the U.S.-Japan Cooperative Medical Science Program; the National Cancer Center Research and Development Fund; a grant for priority areas from the Japanese Ministry of Education, Culture, Sports, Science and
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