ORIGINAL ARTICLE
A Case of NUT Midline Carcinoma With Complete Response
to Gemcitabine Following Cisplatin and Docetaxel
Hideaki Ueki, MD,*w Naoko Maeda, MD, PhD,* Masahiro Sekimizu, MD, PhD,*
Yuka Yamashita, MS,z Suzuko Moritani, MD, PhD,y and Keizo Horibe, MD, PhD*z
Background: NUT midline carcinoma (NMC) is recognized as a
very rare tumor that most often occurs around the midline and
shows NUT rearrangement. This tumor affects children and
younger adults, progresses rapidly, and shows an extremely poor
prognosis, even with intensive chemotherapy. Very few reports
have described effective treatment for this tumor.
Methods: A 12-year-old girl with NMC was treated using cisplatin
(CDDP), docetaxel, gemcitabine, pemetrexed, and vinorelbine.
Results: Imaging showed partial response with CDDP and docetaxel, and complete response with gemcitabine. After reexacerbation of the tumor, although partial response was achieved
with vinorelbine, the patient died 89 weeks after onset because of
reexacerbation.
Conclusions: NMC is a very rare disease with poor prognosis. This
study is the first to report response of NMC to gemcitabine and
vinorelbine. The findings suggest that combination chemotherapies
including CDDP, docetaxel, gemcitabine, and vinorelbine may be a
choice in the treatment for NMC.
Key Words: NUT midline carcinoma, docetaxel, gemcitabine,
vinorelbine
(J Pediatr Hematol Oncol 2014;36:e476–e480)
C
arcinoma with t(15;19) was first reported as a carcinoma of the thymus by Kubonishi et al in 1991,1 and
later it was described to be a lethal carcinoma in children
and young adults, mostly occurring in structures around
the midline, such as the pharynx, thymus, and trachea.2
Recently, it has been called as NUT midline carcinoma
(NMC), because a rearranged NUT (nuclear protein in the
testis) gene on chromosome 15q14 was identified in carcinoma with t(15;19). In most cases, NUT is involved in a
balanced translocation with the BRD4 gene on chromosome 19p13.1, creating a BRD4-NUT fusion transcript.
Histologic characteristics includes squamous differentiation
recognized in most NMCs,3 and undifferentiated basaloid
cells with focal squamoid differentiation with strong
immunohistochemical staining of cytokeratins and p63.4
There have been few reports that describe any effectiveness
of chemotherapy for NMCs. Here we report a case of NMC
Received for publication May 28, 2013; accepted November 12, 2013.
From the Departments of *Pediatrics; yPathology; zClinical Research
Center, National Hospital Organization Nagoya Medical Center,
Nagoya, Aichi; and wDepartment of Pediatrics, Japanese Red
Cross Narita Hospital, Narita, Chiba, Japan.
The authors declare no conflict of interest.
Reprints: Hideaki Ueki, MD, Department of Pediatrics, Japanese Red
Cross Narita Hospital, Iida-cho 90-1, Narita, Chiba 286-8523,
Japan (e-mail: [email protected]).
Copyright r 2013 by Lippincott Williams & Wilkins
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with complete response to gemcitabine following cisplatin
(CDDP) and docetaxel.
CASE PRESENTATION
A 12-year-old girl presented to a neighboring hospital with a
4-month history of increasing back pain, emaciation, and facial
pallor. Pneumonia was initially suspected with the findings of right
hilar infiltration by chest radiography and elevated C-reactive
protein. Because of the ineffectiveness of antibiotics, further
investigations were carried out. Computed tomography (CT)
revealed a right hilar mass, and bronchoscopy indicated irregularity and distended blood vessels on the surface of the right main
stem bronchus. A small piece of tumor tissue was available by
transbronchial biopsy. The tumor showed aggregates of small
round cells with inconspicuous cytoplasm. Immunohistochemically, they were positive for low molecular weight cytokeratin
(CAM5.2), and negative for pancytokeratin (AE1/AE3), epithelial
membrane antigen, vimentin, desmin, myogenin, CD56, chromogranin, synaptophysin, CD45, CD20, CD30, terminal deoxynucleotidyl transferase, and thyroid transcription factor-1.
One month after the first visit to the previous hospital, the
patient was referred to our hospital. She presented neck stiffness
and tenderness, a lymph node 1 cm in diameter palpable in the right
supraclavicular fossa, coarse crackles in the right lower pulmonary
lobe, and hepatomegaly. Blood chemistry showed elevated levels of
lactate dehydrogenase (557 IU/L), alkaline phosphatase (1827 IU/
L), and C-reactive protein (11.44 mg/dL). CT confirmed tumor
growth on the right clavicle, upper mediastinum, tracheal bifurcation, and right hilum, compressing the trachea, with a maximum
diameter of 5 cm (Fig. 1). As the previous transbronchial biopsy
was insufficient for the definitive pathologic diagnosis, excisional
biopsy of the tumor in the right supraclavicular fossa was conducted. The tumor demonstrated invasive growth of irregular
sheets or nests of immature basaloid cells with frequent squamous
differentiation at the center. Immunohistochemically, the undifferentiated basaloid tumor cells were diffusely and strongly positive
for pancytokeratin (AE1/AE3), low molecular weight cytokeratin
(CAM5.2), and p63, which is a marker of basal cells. High
molecular weight cytokeratin (34bE-12) was preferentially positive
in the areas of squamous differentiation. Although CD56, which is
one of the neuroendocrine markers, was positive, other neuroendocrine markers including chromogranin-A, synaptophysin,
neurofilament, and S-100 were all negative (Fig. 2). BRD4-NUT
fusion genes were detected by dual-color fluorescence in situ
hybridization (FISH; Fig. 3).
With regard to the treatment, ifosfamide (IFM) at 2 g/m2/d
for 5 days and doxorubicin (DOX) 20 mg/m2/d for 3 days were first
administered with the consideration of synovial sarcoma or desmoplastic small round cell tumor based on the findings of transbronchial biopsy. However, as the tumors did not respond at all, a
regimen of CDDP at 25 mg/m2 (days 1 to 3) and docetaxel at
60 mg/m2 (day 1) were indicated in reference to the treatment for
non–small cell lung carcinoma (NSCLC).5,6 The outcome was
partial response with a decrease in sum of the longest diameters of
measurable tumors from 104 to 70 mm (Fig. 4). After the 5th
course of CDDP and docetaxel with stable disease, gemcitabine at
1000 mg/m2 was administered 3 times weekly, resulting in complete
response (Fig. 4). However, after the fifth course of gemcitabine, a
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NUT Midline Carcinoma With Response to Gemcitabine
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D
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FIGURE 1. Imaging on hospitalization. A, Chest x-ray. Infiltrative shadows at the hilum of the right lung (arrow). B, Chest CT. Infiltrative
shadow seen in right lung field (arrow). C, Contrast-enhanced CT of the chest. A 5-cm mass is apparent in the right, upper mediastinum
(arrow). (D) Contrast-enhanced CT of the chest. A 2 1.5-cm mass is seen in the hilum of the right lung (arrow). CT indicates computed
tomography.
relapsed lesion in S4 and S5 of the right lung was revealed by
positron emission tomography with computed tomography (PETCT). Duration of the overall response was 170 days. Although
relapsed tumors were resected, multiple metastases in the vertebrae,
pelvis, and liver were revealed by PET-CT after 3 doses of pemetrexed at 500 mg/m2 every 3 weeks. Then, chemotherapy was
changed to vinorelbine at 25 mg/m2 weekly, resulting in a partial
response by PET-CT after 8 doses of vinorelbine. One month later,
multiple liver metastases were revealed by CT. She gradually
deteriorated and died of liver failure another month later.
DISCUSSION
NMC is a tumor associated with rearrangement of
the NUT gene on chromosome 15. Typically, t(15;19)
(q13.2;p13.1) is observed, resulting in the formation of a
BRD4-NUT fusion gene. Less commonly, NMC harbors
a different rearrangement involving NUT, for example,
BRD3-NUT.7 The fusion gene has been suggested to be
associated with cellular immortalization and inhibition of
epithelial differentiation, possibly by sequestering histone
acetyltransferase activity.7,8 This rare tumor most frequently occurs in children and young adults, involving
organs near the midline often on the supra-diaphragm, such
as in the pharynx, thymus, or respiratory tract. The cellular
origin remains unclear, although one theory posits that
NMC arises from a remnant of an early epithelial progenitor cell. The clinical course is extremely aggressive, and the
mean duration of survival is 28 weeks. In a study by French
et al,2,7 of the 11 patients with NMC and a squamous cell
component, 10 patients died, whereas 1 patient remained
alive with the tumor for 100 weeks.
French stated that the histologic features of NMC are
not diagnostic. The morphology is that of poorly differentiated carcinoma, with or without squamous differentiation, distinctly monomorphic, clonal appearance is
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seen, contrasting with the garden variety poorly differentiated carcinoma, which tends to be pleomorphic. NMC
is a new disease, and is not broadly known to most pathologists, and is therefore commonly undiagnosed, or misdiagnosed.9 In addition, in our patient, transbronchial
biopsy findings revealed the basaloid cells that were scattered, and thus the lesion was treated as small round cell
tumor. Thus, incision biopsy is important to conduct if at
all possible, and a good quality specimen needs to be
obtained.
Rearrangement of the NUT gene was demonstrated by
FISH for all NUT variants or RT-PCR for BRD3-NUT or
BRD4-NUT fusion transcripts.3,5,9 In terms of practical
convenience, a diagnostic monoclonal antibody to NUT
with 87% sensitivity and 100% specificity is available for
routine diagnosis.9,10
No treatment for NMC as yet been established, and
only a few reports have suggested effective treatments.
Engleson and colleagues reported the case of a 30-year-old
woman with mediastinal NMC containing a squamous cell
component. She was first treated with chemotherapy using
vincristine, IFM, DOX, and etoposide. After tumor
regrowth, 30 Gy of mediastinal irradiation and docetaxel at
30 mg/m2/wk were administered and their effectiveness was
demonstrated on autopsy 3 weeks later.5 Mertens and colleagues described the case of a 10-year-old boy with ileac
bone Ewing sarcoma and positive results for BRD4-NUT
fusion gene, but no positive results for any epithelial
markers, differing markedly from previous reports. The
patient remained alive and well for a long time after
treatment with an SSG IX protocol containing vincristine,
DOX, IFM, and CDDP.11 These reports suggest that
quantitative differences in epithelial components may alter
chemosensitivity. Recently, Bauer et al12 reported that a
gross total surgical resection and initial radiotherapy are
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FIGURE 2. Biopsy of the right supraclavicular lymph node. A, HE staining. A tendency toward squamous epithelial differentiation
(arrow), and immature basaloid cells (arrowhead) can be seen. B, HE staining. Immature basaloid cells (arrow) make up the majority of
cells. C, Immunostaining with p63. Most cells are p63-positive (representing immature basaloid cells).
independently predictive of progression-free survival and
overall survival, whereas no chemotherapeutic regimen was
associated with improved outcome. They recommended
intensive local therapy such as gross total resection and
radiotherapy. In the present case, IFM + DOX treatment
was first administered without any response. Second,
treatment in accordance with NSCLC treatment and the
NMC treatment previously reported was carried out.
Schiller et al6 described that regimens of CDDP and
paclitaxel, CDDP and gemcitabine, CDDP and docetaxel,
or carboplatin and paclitaxel have been similarly effective
for NSCLC. Engleson et al5 showed docetaxel was effective
against NMC with squamous cell components. On the basis
of these reports, we treated this patient with CDDP +
docetaxel with partial response. After that, gemcitabine
administered in accordance with NSCLC treatment produced complete response. Furthermore, partial response
was obtained by vinorelbine at the time of following
relapse. This is probably the first report of NMC
responding to gemcitabine and vinorelbine, as far as we
searched.
Recently, differentiation therapy was proposed on the
basis of the sequestration model for BRD-NUT proteins by
French.7 In fact, they showed that Food and Drug
Administration in the United States (FDA)-approved histone deacetylase inhibitor, vorinostat, exhibited antitumor
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activity in a pediatric patient with NMC.8 Furthermore, a
new class of inhibitors that bind competitively to the acetylhistone-binding pocket of bromodomain and extraterminal
bromodomains were found to induce rapid differentiation
and growth arrest of cultured NMC cells and its activity
was also observed in vivo in the NMC xenograft models.13
The combined effects of histone deacetylase inhibitor and
bromodomain and extraterminal inhibitor might be
expected.
Thus, we should consider a possibility of NMC and
examine BRD4-NUT FISH or immunohistochemical
staining for NUT, if atypical carcinoma is found near the
midline in children or young adults. As NMC is a very rare
disease with poor prognosis, worldwide collaborative
efforts are necessary to achieve diagnostic and therapeutic
improvement. With regard to the treatment, combination
chemotherapies including CDDP, docetaxel, gemcitabine,
and vinorelbine may be a choice in the treatment for NMC,
as well as differentiation therapy including vorinostat. They
are warranted to be challenged in the future.
ACKNOWLEDGMENT
The authors thank Dr Yukichi Tanaka of the Division of
Pathology at Kanagawa Children’s Medical Center for his
invaluable advice in the diagnosis of this patient.
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NUT Midline Carcinoma With Response to Gemcitabine
FIGURE 3. Detection of BRD4-NUT fusion gene. The most frequently observed NUT rearrangement of NMC is the BRD4-NUT fusion
gene. To confirm the diagnosis of NMC, FISH analysis was performed using NUT and BRD4 BAC clones (Advanced GenoTechs, Tsukuba,
Japan) on paraffin-embedded sections of biopsy samples from the right supraclavicular lymph node. RP11-602M11/RP11-194H7 and
RP-11637P24/RP1174L8 were mixed together and used for the BAC for the NUT and BRD4 loci, respectively. The BRD4-NUT fusion gene
(arrowhead) was seen in 117 of the 183 cells analyzed (64%). FISH indicates fluorescence in situ hybridization; NMC, NUT midline
carcinoma.
FIGURE 4. Treatment response in chest CT. A, After 5 courses of CDDP + docetaxel. The mass has shrunk, but remains in the right upper
mediastinum. B, After 5 courses of CDDP + docetaxel. The mass in the hilum of the right lung has shrunk. C, After 4 courses of
gemcitabine, the mass in the hilum of the right lung has shrunk further. CT indicates computed tomography.
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REFERENCES
1. Kubonishi I, Takehara N, Iwata J, et al. Novel t(15;19)(q15;
p13) chromosome abnormality in a thymic carcinoma. Cancer
Res. 1991;51:3327–3328.
2. French CA, Kutok JL, Faquin WC, et al. Midline carcinoma
of children and young adults with NUT rearrangement. J Clin
Oncol. 2004;22:4135–4139.
3. French CA. Demystified molecular pathology of NUT midline
carcinomas. J Clin Pathol. 2010;63:492–496.
4. Den Bakker MA, Beverloo BH, van den Heuvel-Eibrink MM,
et al. NUT midline carcinoma of the parotid gland with
mesenchymal differentiation. Am J Surg Pathol. 2009;33:1253–1258.
5. Engleson J, Soller M, Panagopoulos I, et al. Midline carcinoma
with t(15;19) and BRD4-NUT fusion oncogene in a 30-year-old
female with response to docetaxel and radiotherapy. BMC
Cancer. 2006;6:1–5.
6. Schiller JH, Harrington D, Belani CP, et al. Comparison of
four chemotherapy regimens for advanced non-small-cell lung
cancer. N Engl J Med. 2002;346:92–98.
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7. French CA. Pathogenesis of NUT midline carcinoma. Annu
Rev Pathol. 2012;7:247–265.
8. Schwartz BE, Hofer MD, Lemieux ME, et al. Differentiation
of NUT midline carcinoma by epigenomic reprogramming.
Cancer Res. 2012;18:5773–5779.
9. French CA. NUT midline carcinoma. Cancer Genet Cytogenet.
2010;203:16–20.
10. Haack H, Johnson LA, Fry CJ, et al. Diagnosis of NUT
midline carcinoma using a NUT-specific monoclonal antibody.
Am J SurgPathol. 2009;33:984–991.
11. Mertens F, Wiebe T, Adlercreutz C, et al. Successful treatment
of a child with t(15;19)-positive tumor. Pediatr Blood Cancer.
2006;10:1015–1017.
12. Bauer DE, Mitchell CM, Strait KM, et al. Clinicopathologic
features and long-term outcomes of NUT midline carcinoma.
Clin Cancer Res. 2011;71:5773–5779.
13. Filippakopoulos P, Qi J, Picaud S, et al. Selective inhibition of
BET bromodomains. Nature. 2010;468:1067–1073.
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