Pediatric NUT Carcinoma Is a Rare and Challenging Tumor: Single Center Experience of Five Children

This brief communication describes the clinical characteristics and outcomes of five children with nuclear protein of the testis carcinoma (NUT) carcinoma.

Abstract

Background.

Nuclear protein of the testis (NUT) carcinoma is a rare and aggressive malignancy associated with rearrangements of the nuclear protein of the testis (NUT) gene on chromosome 15q14. Because of its rarity, this tumor is often underdiagnosed and underreported, and there is limited literature regarding its biology and optimal management.

Methods and Results.

We report our experience of five patients with pediatric NUT carcinoma, all of whom presented with midline head and neck mass. In spite of aggressive multimodality treatment, only one patient survives.

Conclusion.

NUT carcinoma has a dismal prognosis in spite of aggressive multimodality management (surgery and adjuvant chemotherapy and/or radiation). Novel strategies are required to improve outcomes of patients with this tumor.

Introduction

Nuclear protein of the testis (NUT) carcinoma is a recently defined rare and aggressive malignancy with a histology of poorly differentiated squamous cell carcinoma, associated with rearrangements of the nuclear protein of the testis (NUT) gene on chromosome 15q14 [1], [2], [3]. The most common chromosomal translocation, t(15;19)(q13;p13), is seen in 70%–80% cases and results in the BRD4‐NUT fusion gene, with several further fusion variants also having been described [1].

These tumors are characteristically (but not exclusively) seen in the midline, mainly head, neck, and mediastinum, hence the older name of NUT midline carcinoma. NUT carcinoma was originally described in adolescents and young adults but can occur at any age and is rare in young children [4], [5]. First described in 1999, NUT carcinoma is probably underdiagnosed, with most literature being single case reports and small case series. However, larger case series, including those from the International NUT Midline Carcinoma Registry, have contributed to our understanding of the biology of this entity [4], [5], [6], [7], [8]. Prognosis of NUT carcinoma is generally poor in spite of aggressive multimodality management, which incorporates surgery and adjuvant chemotherapy and/or radiation [5], [8].

In this paper, we describe the clinical characteristics and outcome of children with NUT carcinoma diagnosed and treated at our center over the past 5 years.

Patients and Methods

This study was a retrospective analysis of all pediatric patients (aged less than 18 years) diagnosed with NUT carcinoma at Tata Memorial Hospital Mumbai between January 1, 2014, and December 31, 2018. NUT carcinoma was diagnosed on histology and immunohistochemistry, with positive immunostaining for NUT antibody being mandatory [9]. For the purpose of this study, the histology and radiology were reviewed by a pediatric onco‐pathologist and pediatric radiologist, respectively. Information such as demographics (including age, gender, and presentation), radiological staging, treatment details, and outcome data were extracted from the prospectively maintained database and electronic medical records. Patients with NUT carcinoma either suspected clinically or on histopathology, but without immunohistochemistry confirmation, were excluded from this analysis even though the diagnosis of midline carcinoma may have been considered. All data analyses were carried out using SPSS Statistics for Windows, version 20.0. (IBM SPSS, Chicago, IL). Overall survival (OS) was calculated from the date of diagnosis to the date of death or the last follow‐up visit, and event‐free survival (EFS) was calculated from the date of diagnosis to the date of relapse, progression, or death from any cause. Kaplan‐Meier product‐limit estimator analyzed EFS and OS estimates. The Institutional Ethics Committee has approved this study.

Results

Over the 5‐year study period, 22 patients of all ages were diagnosed to have NUT carcinoma based on clinical and/or radiological presentation and histology; 14 of 22 stained positive for NUT antibody. The median age of confirmed cases was 39 years (range 9–61 years) with a female‐to‐male ratio of 4:3. Of the six children (aged less than 18 years), five had a confirmed diagnosis of NUT carcinoma after review of histology with positive NUT antibody staining. Three were female and two were male, with a median age of 11 years (range 9–17 years). All presented with head and neck mass: three presenting as nasal masses, one as orbital mass, and the last as laryngeal mass. All patients underwent staging by 18‐fluorodeoxyglucose positron emission tomography scan at diagnosis and progression). In all children, primary tumors were locally extensive midline tumors, and one additionally had distant metastasis in the form of multiple bone cortical and marrow metastasis, lung, and retroperitoneal node involvement. Three of five patients had been incorrectly diagnosed prior to coming to our center, with the median time to reach the correct diagnosis being 2 months. Table 1 describes the characteristics of patients described in this study, and Figure 1 shows salient imaging findings of three patients in this study.

Table 1. Clinical profile and outcomes of patients with pediatric NUT carcinoma in this series.

Abbreviations: #, fraction; CT, chemotherapy; EFS, event‐free survival; F, female; Gy, gray; IC, intracranial; M, male; N/A, details not available; NUT, nuclear protein of the testis; OS, overall survival; PNS, paranasal sinus; RT, radiation therapy; SF, single fraction; Sx, surgery.

Figure 1.

Salient findings on imaging of some patients in this series. (A): Axial contrast‐enhanced computed tomography (CECT) and fused positron emission tomography–computed tomography (PET/CT) images of Patient 2 reveal a large heterogeneous fluorodeoxyglucose (FDG)‐avid right orbital mass also involving the right maxillary sinus and the right nasal cavity. The mass also involves the overlying subcutaneous tissue and crosses the midline to the left. (B): Axial CECT and fused PET/CT images of Patient 3 reveal a large heterogeneous partially calcific mass epicentered in the nasal cavity, with intracranial extradural extension to the right anterior temporal region. The right orbital apex is also involved. Maximum intensity projection images demonstrate diffuse skeletal metastases. (C): Axial CECT and fused PET/CT images of Patient 5 demonstrate an FDG‐avid enhancing left nasal cavity mass involving the medial maxillary wall and also crossing the midline to the right nasal cavity.

All patients except one received multimodality treatment. Subsequent to reports suggesting the survival benefit of complete surgical excision, two children underwent extensive surgery in the form of orbital exenteration and total maxillectomy; the first received two cycles of neoadjuvant chemotherapy and progressed immediately after surgery; the second received adjuvant radiation to a dose of 59.4 Gy and continues to be in remission 21 months after diagnosis. Only debulking surgery was possible in the third patient because of extensive locoregional disease; he received adjuvant radiation of 70.2 Gy and two cycles of adjuvant chemotherapy but progressed after 2 months. In the fourth patient, who had presented with an epiglottic mass, the disease was inoperable because of location; she received definitive radiation of 70.2 Gy but had a metastatic progression after 3 months. The fifth patient had presented with widely metastatic disease and received a single fraction of radiation and a single dose of chemotherapy, with purely palliative intent. Four patients in our series died of progressive disease with a median progression‐free survival of 3 months and OS of 10 months.

Discussion

The clinical profile of patients in this series corresponds to reported series, namely, aggressive (midline) head and neck tumors with a mild female preponderance, but with a higher median age at presentation of 39 years [5], [8]. Rarity of this tumor meant that three of five patients had an incorrect initial diagnosis (one was labeled “undifferentiated carcinoma” without further specification). Outcome of patients in this series has been poor, with only one survivor, corresponding to the uniformly dismal prognosis of this tumor with reported median OS being 4.7–9.5 months and median EFS 1.9–6.6 months [5], [7]. Because of the small number of patients in this series, we are unable to make a conclusion regarding effective treatment options. Treatment approaches have been very heterogeneous even in literature, and a recent report of two pediatric patients reports the success of a multimodality sarcoma‐based approach [3]. Our strategy of combination chemotherapy with taxane‐platinum yielded only transient response. Although complete and aggressive surgery has been recommended, these tumors tend to be inoperable because of location, which was the case in three of five patients in our series [5], [8]. The only survivor in our series had a locally extensive nasopharyngeal mass that could be completely excised and subsequently received adjuvant radiation; however, the follow‐up of 15 months is too short for us to make a definite conclusion.

The presence of a specific chromosomal translocation has made targeted therapy a promising adjunct or alternative to conventional treatment. Ongoing clinical trials with targeted therapy are investigating the use of drugs such as BRD inhibitors, BET inhibitors, and HDAC inhibitors [10], [11], [12]. Early and accurate diagnosis and better understanding of biology and natural history are essential to improve therapeutic approaches in this rare tumor.

Disclosures

The authors indicated no financial relationships.