Gynecologic Oncology Reports 3 (2013) 1–3

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Gynecologic Oncology Reports journal homepage: www.elsevier.com/locate/gynor

A rare case of NUT midline carcinoma Allison Ball a,⁎, Amy Bromley b, Sarah Glaze a, Christopher A. French c, Prafull Ghatage a, Martin Köbel b a b c

Division of Gynecologic Oncology, Tom Baker Cancer Centre, Calgary, AB, Canada Department of Pathology and Laboratory Medicine, University of Calgary, Calgary, AB, Canada Department of Pathology, Brigham and Women's Hospital, Boston, MA, USA

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Article history: Received 11 July 2012 Accepted 28 September 2012 Available online 8 October 2012 Keywords: NUT midline carcinoma NMC Cancer Thoracic mass

Introduction NUT midline carcinoma is a rare aggressive carcinoma arising in midline structures. The most common areas of diagnosis are the head and neck region and mediastinum. There are only 62 known cases and this is the second case describing the involvement of gynecologic structures (French et al., 2004; French, 2012). This tumor is refractory to conventional treatments, with a median survival of 6.7 months and an overall survival of 19% at 2 years(Bauer et al., 2012). However, since the key molecular alteration is known promising research is emerging with the goal to overcome differentiation arrest in these tumors. Case A 19 year old female presented with a three month history of an increase in shortness of breath, cough, and pelvic discomfort. Chest x-ray showed an opacity in the left superior mediastinum. A CT scan of the chest, abdomen, and pelvis revealed masses in both the chest and pelvis. The chest contained a solid mass measuring 11 cm× 7.5 cm within the left lung encasing the left pulmonary artery and distal bronchial tree somewhat arising from the mediastinum. The pelvis contained a multilobular complex mass measuring 15 cm× 12 cm at the left adnexa (Fig. 1B). She was transferred to the Gynecologic Oncology service, Tom Baker Cancer Center, Calgary AB. Tumor markers ⁎ Corresponding author. E-mail addresses: [email protected], [email protected] (A. Ball).

were elevated: AFP= 326 μg/L, Ca 125 = 146 kU/L, LDH = 1982 U/L, and bHCG of b 1 IU/L. The thoracic mass was targeted by biopsy but was non-diagnostic. She subsequently underwent a laparotomy with left salpingoophorectomy, left pelvic lymph node dissection and removal of a 5 cm paraaortic lymph node. With respect to her intraabdominal disease, she was considered optimally debulked to microscopic disease. An intraoperative pathologic consultation of the pelvic mass was interpreted as a poorly differentiated neoplasm with extensive necrosis. On permanent histology, an undifferentiated carcinoma with focal squamous differentiation was diagnosed (Figs. 2A and B). In light of the elevated tumor markers, extensive sampling was performed but did not reveal any germ cell tumor component (yolk sac, embryonal, dysgerminoma, or teratoma). A battery of immunohistochemical markers was applied but was non informative with the exception of diffuse p63 expression supporting squamous cell lineage. Despite the young age, malignant transformation of a somatic tumor overgrowing a teratoma was considered. . Other differential diagnosis occurring in this age group included the large cell variant of small cell carcinoma of hypercalcemic type (diligent search failed to show typical follicles, WT1 negative) and other small cell malignant tumors such as metastatic melanoma (S100 negative) and primitive neuroectodermal tumor (PNET, CD99 negative). But the lack of typical morphological features (the tumor cells were not particularly small) or immunohistochemical marker negativity precluded these diagnoses. The patient received four cycles of bleomycin, etopiside, and cisplatin. The thoracic mass initially decreased in size from chemotherapy. However, ongoing investigations deemed the mass unresectable and not amenable to bronchial stenting. Repeated attempts at biopsy of the thoracic mass resulted in further necrotic tissue and atypical cells suspicious for malignancy, but no definitive diagnosis. She subsequently developed a pericardial effusion. The thoracic mass continued to enlarge to virtually replace the entire left lung, and the patient developed progressive respiratory symptoms (Fig. 1A). She had ongoing shortness of breath, increasing mediastinal deviation, and tumor invasion involving the chest wall. She underwent a course of palliative radiation therapy to the chest (20 Gray over 5 days) and was started on carboplatin and paclitaxel. The patient received only one cycle before developing febrile neutropenia, electrolyte disturbances, and anemia. Over the subsequent two weeks she developed progressive cardiothoracic symptoms, including unstable tachyarrhythmias and hypoxemia. At this time a decision was made to treat her palliatively. She passed away peacefully five months after her diagnosis of cancer. Permission was granted for an autopsy.

2211-338X/$ – see front matter. Crown Copyright © 2012 Published by Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.gynor.2012.09.004

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Fig. 1. A. Coronal CT image of the chest during chemotherapy treatment, indicating marked adverse change from time of diagnosis. There is encasement of the aorta and great vessels, and occlusion of the pulmonary veins and left mainstem bronchus. The mass measures approximately 10 cm by 11 cm and there are multiple loculations of fluid and tumor contributing to the pronounced mediastinal shift. B. Coronal CT image of the abdomen and pelvis at the time of diagnosis. There is a complex multilobular pelvic mass arising from the left ovary measuring 15 cm × 12 cm. Also noted is a paraaortic nodal mass measuring 5 cm.

Autopsy was revealed extensive metastases involving the mediastinum, heart, pericardium, left lung, left hemidiaphragm, left peri-renal fat, mesenteric root, small and large intestine (Fig. 3) associated with pericardial and pleural effusion, and left hydronephrosis. The histology of the tumor at autopsy was identical to that of the pelvic mass with sheets of poorly differentiated, extensively necrotic carcinoma with small foci of abrupt squamous differentiation. Discussion of the case and evaluation of the literature led to the possibility that the tumor was a NUT midline carcinoma (French et al., 2003). External consultation was sought with the International Nut Midline Carcinoma Registry at the Brigham and Woman's Hospital. The diagnosis of NUT midline carcinoma with BRD4-NUT fusion was made after demonstration of diffuse nuclear immunohistochemical staining with NUT protein (Fig. 2C), and by fluorescent in situ hybridization, performed as described (Fig. 2C, inset) (Haack et al., 2009).

Discussion NUT midline carcinoma (NMC) is a rare aggressive cancer of squamous cell lineage arising in midline structures. NMC are not classified according to the tissue/site of origin as with the majority of solid tumors, but are rather defined genetically. The cytogenetics of NMC are less complex than of typical squamous cell carcinomas. The characteristic cytogenetic abnormality is a reciprocal translocation of the NUT (nuclear protein in testis, AKA Chr15orf55) gene on the long arm of chromosome 15 with one of the BET family members, most commonly BRD4 (also known as MCAP and HUNK1) on chromosome 19p13.1 (t(15;19)(q14;p13.1)) (Bauer et al., 2012 Sep 17). This results in a fusion oncogene (BRD4-NUT) which arrests normal cellular differentiation (French et al., 2008). The NUT translocation can be diagnosed using karyotype, FISH or RT-PCR. A monoclonal antibody

Fig. 2. A. Non-specific sheet of medium size, slightly discohesive tumor cells with prominent nucleoli, limited nuclear variability and high mitotic activity. B. Focus of abrupt keratinization indicating squamous differentiation. (H&E, 400×) C. Immunohistochemistry of tumor cell nuclei showing speckled staining for NUT. Inset: Dual color, dual fusion FISH on formalin-fixed, paraffin-embedded sections reveals tetraploid tumor cell nuclei with fusion of NUT spanning probes (red) to BRD4 spanning probes (green). Single green and red signals are the normal alleles of BRD4 and NUT, respectively. Not all signals are present per nucleus because these are thin sections (4 μm).

A. Ball et al. / Gynecologic Oncology Reports 3 (2013) 1–3

Fig. 3. Autopsy picture of the open thorax exposing extensive tumor involving the left thorax and cardiac structures.

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associated with increased gene transcription and differentiation, is to block the endogenous action of histone deacytelases. Recent research that utilizes therapeutic histone deacetylase inhibitors (HDACi) to derepress differentiation of the NMC cells appears promising. Cell lines of NUT carcinoma cells and murine models have responded to various HDACi. Vorinostat, a HDACi, was used in the case of a 10-year old boy with a NUT midline carcinoma. He was treated for five weeks and had an objective clinical response before toxicities limited its continued use. After stopping the drug, the disease recurred and he died eleven months after diagnosis. Despite the inability to achieve cure in his case, HDACi use remains a focus of ongoing clinical research in treating this disease (Schwartz et al., 2011). The case presented here is a rare case of a NUT midline carcinoma involving gynecologic structures. However her concurrent thoracic mass posed the greater clinical challenge and was unresectable at presentation. Despite some initial response, it became refractory to treatment and was ultimately the cause of her rapid decline and death. This case brings to light this rare tumor as a possible etiology when an aggressive, poorly differentiated carcinoma is identified, and serves an example in which the knowledge about the underlying molecular alterations can serve as guide towards developing an effective treatment for this devastating disease. Conflict of interest statement The authors declare that there are no conflicts of interest.

for use in immunohistochemistry has been developed for widespread application.(Haack et al., 2009). The immunohistochemical assay can detect the NUT protein in NMC, whose expression in normal mature adult tissue is restricted to the testis. With the use of the immunohistochemical assay it became clear that NMC is not restricted to younger patients but affects all age groups (French, 2012). NMC is often widely metastatic and unresectable when diagnosed. All known cases of NMC have had a poor clinical course with a mean survival of approximately nine months. The histological diagnosis is usually that of poorly differentiated or squamous cell carcinoma but occasionally has been classified as other tumors, e.g. thymic carcinoma. As in our case these tumors are virtually refractory to radiation and chemotherapy. However, growing understanding about the function of the key molecular alteration does show promising approaches to overcome the differentiation arrest. The normal function of NUT is hypothesized to aid chromatin compaction during spermatogenesis and interfering with the balance of histone acetylation/deacetylation. One means to bring the chromatin into a more relaxed state, which is

References Bauer, D.E., Mitchell, C.M., Strait, K.M., Lathan, C.S., Stelow, E.B., Lüer, S.C., et al., 2012. Clinicopathologic features and long-term outcomes of NUT midline carcinoma. Clin. Cancer Res. (Sep 17. [Epub ahead of print]). French, C.A., 2012. Pathogenesis of NUT midline carcinoma. Annu. Rev. Pathol. 7, 247–265. French, C.A., Miyoshi, I., Kubonishi, I., Grier, H.E., Perez-Atayde, A.R., Fletcher, J.A., 2003. BRD4-NUT fusion oncogene: a novel mechanism in aggressive carcinoma. Cancer Res. 63, 304–307. French, C.A., Kutok, J.L., Faquin, W.C., Toretsky, J.A., Antonescu, C.R., Griffin, C.A., et al., 2004. Midline carcinoma of children and young adults with NUT rearrangement. J. Clin. Oncol. 22, 4135–4139. French, C.A., Ramirez, C.L., Kolmakova, J., Hickman, T.T., Cameron, M.J., Kutok, J.L., et al., 2008. BRD-NUT oncoproteins: a family of closely related nuclear proteins that block epithelial differentiation and maintain the growth of carcinoma cells. Oncogene 27, 2237–2242. Haack, H., Johnson, L.A., Fry, C.J., Crosby, K., Polakiewicz, R.D., Stelow, E.B., et al., 2009. Diagnosis of NUT midline carcinoma using a NUT-specific monoclonal antibody. Am. J. Surg. Pathol. 33, 984–991. Schwartz, B.E., Hofer, M.D., Lemieux, M.E., Bauer, D.E., Cameron, M.J., West, N.H., et al., 2011. Differentiation of NUT midline carcinoma by epigenomic reprogramming. Cancer Res. 71, 2686–2696.

A rare case of NUT midline carcinoma.

► NUT midline carcinoma is a rare and aggressive cancer arising in midline structures and is of squamous cell lineage. ► Diagnosis by use of molecular...
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