NUT Carcinoma in a Patient with Unusually Long Survival and False Negative FISH Results.

Nuclear protein in testis (NUT) carcinoma is a rare and highly aggressive epithelial malignancy defined by rearrangement of the NUTM1 gene on chromosome 15q14. Histologically, NUT carcinoma is an undifferentiated carcinoma formed by sheets and nests of primitive and monotonous "round blue cells" with foci of abrupt keratinization in a subset. NUT carcinoma runs a fulminant clinical course and is almost always quickly lethal, with a median overall survival of only 6.7 months. There is no consensus regarding treatment for this disease, and most patients respond poorly to conventional chemotherapy and radiation. We report a case of NUT carcinoma in an African-American man who initially presented in 2009 with a tracheal mass at age 28. Although fluorescence in situ hybridization (FISH) assays for NUTM1 and BRD4 rearrangements were negative, he was diagnosed based on diffusely positive NUT immunostaining and BRD4-NUTM1 on RNA sequencing. Since his initial presentation, he has undergone multiple surgical procedures and radiation therapy. His tumor has recurred twice, but he has survived for 129 months and is currently alive without disease. Long-term survival of patients with NUT carcinoma is incredibly unusual, especially in patients with tumors that exhibit a BRD4 rearrangement. False negative FISH is a pitfall in diagnosing NUT carcinoma; NUT immunostaining and RNA sequencing are more sensitive diagnostic methods.

Primary tracheal synovial sarcoma: a rare clinical entity with diagnostic challenges.

BACKGROUND: The incidence of primary tracheal tumors is very low. Tracheal synovial sarcoma (SS) is even an extremely rare entity. Diagnosis of tracheal SS can be achieved with chromosomal translocation studies along with immunohistochemistry. Margin-free resection is the gold standard treatment. CASE PRESENTATION: We report a case of tracheal SS, which presented with stridor with a history of chronic cough and was diagnosed with a battery of clinical investigations and managed successfully with tracheal resection surgery. In histology, it may mimic Ewing's sarcoma. Immunohistochemically, SS stains positive for cytokeratin, epithelial membrane antigen, vimentin, and S100. Chromosomal translocation t(X;18) (p11;q11) is found in almost all SS. This genetic signature is the gold standard diagnostic modality for these tumors. CONCLUSION: Diagnosis of tracheal synovial sarcoma is challenging because of the rarity of the disease and common presenting symptoms to other tracheal pathology and is supplemented with chromosomal translocation study along with histopathology and immunohistochemistry. Tumor coring before definite surgical resection facilitates lung perfusion in obstructive tracheal pathology. A multidisciplinary team approach for diagnosis and management along with long-term follow-up are warranted.

Detecting MYB and MYBL1 fusion genes in tracheobronchial adenoid cystic carcinoma by targeted RNA-sequencing.

Primary tracheobronchial adenoid cystic carcinoma is rare, accounting for less than 1% of all lung tumors. Many adenoid cystic carcinomas have been reported to have a specific chromosome translocation t(6;9)/MYB-NFIB. More recently, t(8;9)/MYBL1-NFIB gene fusion was reported in salivary gland adenoid cystic carcinomas which lacked a t(6;9)/MYB-NFIB. Two prior studies showed t(6;9)/MYB-NFIB in tracheobronchial adenoid cystic carcinoma; however, only rare cases of MYBL1 rearrangement have been reported in this carcinoma. In this study, we used targeted RNA sequencing to investigate fusion genes in tracheobronchial adenoid cystic carcinoma at our institution. Fusions of either MYB or MYBL1 genes were detected in 7 of 7 carcinomas. Three cases had MYB-NFIB, and 3 had MYBL1-NFIB. The remaining case showed a rare MYBL1-RAD51B fusion. These findings suggest that rearrangement involving MYB or MYBL1 is a hallmark of tracheobronchial adenoid cystic carcinoma.

IDH mutation status in a series of 88 head and neck chondrosarcomas: different profile between tumors of the skull base and tumors involving the facial skeleton and the laryngotracheal tract.

Chondrosarcomas are rare primary malignant bone tumors that involve the head and neck region in 1% to 12% of cases. Central conventional chondrosarcoma is the most common subtype and is associated with isocitrate dehydrogenase 1 and 2 (IDH1 and IDH2) gene mutations in 50% to 60% of cases. We aimed to define the frequency of IDH1 and IDH2 gene mutations in a multicenter series of 88 cases of chondrosarcoma of the head and neck, including tumors involving the base of the skull (n = 30), the facial skeleton (n = 11), and the laryngeal and tracheal cartilages (n = 47). Petrous bone and cricoid cartilage were the most frequently involved sites for chondrosarcomas of the skull base and laryngotracheal tract (43.3% and 31.9%, respectively). Overall, 64.9% of craniofacial chondrosarcomas featured IDH mutations, with a high rate for skull base tumors (85.7%) but no IDH mutations in tumors of the facial skeleton. This different mutational profile could be related to the type of ossification, the bones of the base of the skull mainly resulting from endochondral ossification, and those of the face from intramembranous ossification. Conversely, mutation was infrequent in chondrosarcomas involving the laryngeal and tracheal cartilages (11.8% of 47 cases). Evaluation of IDH mutation status may be a useful diagnostic tool for bone tumors of the skull base, which are most often assessable with only small biopsy samples. The low rate of IDH mutations observed in laryngotracheal chondrosarcomas suggests a different mode of tumorigenesis needing further exploration.

c-Myb Overexpression in Cytology Smears of Tracheobronchial and Pulmonary Adenoid Cystic Carcinomas.

AIMS: Adenoid cystic carcinoma (AdCC) is a malignant epithelial neoplasm that occurs rarely in the lower respiratory tract (LRT). AdCC at various sites is associated with the novel fusion transcript MYB-NFIB, along with the overexpression of the Myb protein. The expression of the Myb protein in AdCC of the LRT has not been evaluated much. STUDY DESIGN: Cases of AdCC of the LRT diagnosed on cytology or histology were retrieved from our institutional archives. c-Myb expression was analyzed on immunocytochemistry/immunohistochemistry (ICC/IHC) and was correlated with clinicopathological parameters. RESULTS: Twenty-three samples of AdCC originating from the LRT were included in the study. Four cases were diagnosed on cytology, 3 of which had corresponding histology specimens. The remaining 19 cases had either biopsy or resection. Most of the patients presented with endobronchial mass. The mean age was 49.4 years and a male predominance was seen. ICC and IHC for c-Myb showed positivity in 75 and 59% of the cases, respectively. Western blot was used to validate IHC results. CONCLUSION: AdCC of the LRT is rare and hence poses diagnostic difficulty. Cytology smears can be utilized for c-Myb ICC. The presence of c-Myb immunopositivity in most cases may possibly make Myb a diagnostic biomarker and a therapeutic target for personalized treatment.

Characterization of stem-like cells in mucoepidermoid tracheal paediatric tumor.

Stem cells contribute to regeneration of tissues and organs. Cells with stem cell-like properties have been identified in tumors from a variety of origins, but to our knowledge there are yet no reports on tumor-related stem cells in the human upper respiratory tract. In the present study, we show that a tracheal mucoepidermoid tumor biopsy obtained from a 6 year-old patient contained a subpopulation of cells with morphology, clonogenicity and surface markers that overlapped with bone marrow mesenchymal stromal cells (BM-MSCs). These cells, designated as MEi (mesenchymal stem cell-like mucoepidermoid tumor) cells, could be differentiated towards mesenchymal lineages both with and without induction, and formed spheroids in vitro. The MEi cells shared several multipotent characteristics with BM-MSCs. However, they displayed differences to BM-MSCs in growth kinectics and gene expression profiles relating to cancer pathways and tube development. Despite this, the MEi cells did not possess in vivo tumor-initiating capacity, as proven by the absence of growth in situ after localized injection in immunocompromised mice. Our results provide an initial characterization of benign tracheal cancer-derived niche cells. We believe that this report could be of importance to further understand tracheal cancer initiation and progression as well as therapeutic development.

Cell migration leads to spatially distinct but clonally related airway cancer precursors.

BACKGROUND: Squamous cell carcinoma of the lung is a common cancer with 95% mortality at 5 years. These cancers arise from preinvasive lesions, which have a natural history of development progressing through increasing severity of dysplasia to carcinoma in situ (CIS), and in some cases, ending in transformation to invasive carcinoma. Synchronous preinvasive lesions identified at autopsy have been previously shown to be clonally related. METHODS: Using autofluorescence bronchoscopy that allows visual observation of preinvasive lesions within the upper airways, together with molecular profiling of biopsies using gene sequencing and loss-of-heterozygosity analysis from both preinvasive lesions and from intervening normal tissue, we have monitored individual lesions longitudinally and documented their visual, histological and molecular relationship. RESULTS: We demonstrate that rather than forming a contiguous field of abnormal tissue, clonal CIS lesions can develop at multiple anatomically discrete sites over time. Further, we demonstrate that patients with CIS in the trachea have invariably had previous lesions that have migrated proximally, and in one case, into the other lung over a period of 12 years. CONCLUSIONS: Molecular information from these unique biopsies provides for the first time evidence that field cancerisation of the upper airways can occur through cell migration rather than via local contiguous cellular expansion as previously thought. Our findings urge a clinical strategy of ablating high-grade premalignant airway lesions with subsequent attentive surveillance for recurrence in the bronchial tree.

[Peripheral primitive neuroectodermal tumor of trachea: a case report and review of literatures].

OBJECTIVE: To improve the understanding of tracheal peripheral primitive neuroectodermal tumor (PNET). METHODS: A case of tracheal PNET diagnosed in July 2010 was reported and the related literatures were reviewed. The literature review was carried out respectively with "primitive neuroectodermal tumor", "peripheral" as the search terms in Wanfang med online and PubMed database by September 2011. RESULTS: A case of 63 year-old female patient, who had been misdiagnosed as having chronic pharyngitis, chronic bronchitis and bronchial asthma, was admitted to the hospital because of cough and sputum production for 50 days, and anhelation for 1 month. After admission, the chest computerized tomography showed a space-occupying lesion in the middle of the trachea. Bronchoscopy showed a pedicle neoplasm 4 cm under the subglottic, with integral capsule, smooth surface and rich vascellum. Subsequently, tumor resection under bronchoscope was performed. Pathology report after operation showed infiltration of flake small round malignant cells under bronchial mucosa. Immunohistochemistry showed CD(99)(+), Syn(+) and S-100(+). EWS-FLI-1 fusion transcript was detected by RT-PCR. Accordingly, it was diagnosed as PNET. The symptoms of cough and anhelation were disappeared after operation. So far, there was no local recurrence and distant metastasis with 14 months follow-up. A total of 111 literatures were received in Pubmed, including one of prospective study, one of review, 22 of retrospective study and 87 of case report. Forty literatures and 187 cases in all were received in Wanfang Med Online, including 24 of retrospective study and 16 of case report. But, there were no reports about tracheal PNET. CONCLUSIONS: PNET can occur in the trachea and is easy to be misdiagnosed. To make a definite diagnosis, histopathology and immunohistochemistry are needed and detection of EWS-FLI-1 fusion transcript is a reliable marker for molecular diagnosis. The tracheal pPNET may be different with the pPNETs in other parts, and has a lower-grade invasion and less distant metastasis.

Primary cervical tracheal monophasic synovial sarcoma confirmed by SYT-SSX gene rearrangement.

OBJECTIVE: To review the existing diagnostic modalities and treatment for primary tracheal synovial sarcoma, and to report a case of primary cervical synovial sarcoma arising in the trachea. DESIGN: Retrospective. SETTING: Head and neck surgery unit at a tertiary university centre. PATIENT: One case of primary cervical tracheal monophasic synovial sarcoma diagnosed by SYT-SSX gene rearrangement. INTERVENTION: This patient underwent surgical resection of the synovial sarcoma, together with tracheal resection and primary anastomosis assisted by laryngeal-releasing manoeuvres, without complication. MAIN OUTCOME MEASURES: Clinical, radiographical, pathological and surgical information were collected. RESULT: One year post-operatively, there was no evidence of recurrence. CONCLUSION: Synovial sarcoma arising in the trachea is very rare. Diagnosis is confirmed by demonstrating the SYT-SSX gene rearrangement. The first-line treatment is surgery.

Molecular transformation of recurrent respiratory papillomatosis: viral typing and p53 overexpression.

Recurrent respiratory papillomatosis (RRP) is a histologically benign disease of the larynx, trachea, and bronchi. Here we report on the histologic and molecular characteristics of 7 cases of malignant transformation of RRP to squamous cell carcinoma (SCCA). The clinical histories of 7 patients with RRP who developed SCCA were carefully reviewed. Sequential biopsies were available from 5 of the 7 cases of spontaneous transformation of RRP to SCCA and were reviewed. In addition, p53 protein overexpression and human papillomavirus (HPV) typing for all cases was examined. The average age of patients with juvenile-onset RRP was 3 years, and that of patients with adult-onset RRP was 31 years. The average age of onset of transformation to SCCA was 28 years. All patients had laryngeal involvement with RRP, and 3 of the 7 patients had tracheal extension of disease. Five patients were tracheotomy-dependent. Four of the 7 patients developed SCCA of the lung, while 3 patients developed laryngeal SCCA. There was no consistent histologic progression from squamous papilloma to papilloma with dysplasia, and all but 1 of the SCCAs were well differentiated. The overexpression of p53 protein was variable in each of the 5 patients. We detected HPV types 6/11 in papillomas from 3 patients, and HPV types 6/11, 16/18, and 31/33/51 in a papilloma of a fourth patient. No HPV DNA was detected in papillomas of 2 patients. We found HPV 6/11 in 4 of the carcinomas. We conclude that the spontaneous transformation of RRP to SCCA is not characterized by a histologic progression through dysplasia over time. Transformation can result in the loss of HPV expression. It does not appear that p53 is a molecular marker for monitoring the transformation process. Thus, these cancers may be very difficult to diagnose histologically and clinically early in the course of the transformation of the disease.

Second primary cancers after resection of lung adenocarcinoma with ras gene mutation.

BACKGROUND: Ras gene mutations are associated with a poor prognosis in patients with adenocarcinoma of the lung. However, the association between cases with ras gene mutation and an occurrence of second primary cancer is unknown. MATERIALS AND METHODS: We examined 89 adenocarcinoma of the lung obtained from patients treated by curative resection, and four second primary cancers, for mutation at codons 12, 13, and 61 of three ras oncogenes using polymerase chain reaction and oligonucleotide hybridization techniques. RESULTS: Ras gene mutations were detected in 13 cases. Six patients died from recurrent disease within 3 years. Of the seven patients who survived over 5 years, three patients demonstrated a metachronous second primary cancer after the operation for lung cancer, and one patient had synchronous laryngeal cancer. Two of the cases with second primary cancer demonstrated the ras gene mutation. One had the same mutation as that of the primary lung cancer, and the other had a different mutation from the first lung cancer. CONCLUSION: Ras gene mutations play an important role in tumor progression of lung adenocarcinoma and also might have an role in the carcinogenesis in respiratory tract cancer.

Multiple changes in gene expression are associated with normal cell-induced modulation of the neoplastic phenotype.

Specific regulatory pathways in neoplastic cells seem to be responsive to control signals provided by the normal cell/tissue environment. The present experiments were designed to define, at the molecular level, the growth-regulatory signals in neoplastic cells that are associated with the modulation of expression of the neoplastic phenotype by normal cell populations. When cultured in the presence of normal cell-conditioned medium, a highly malignant rat tracheal carcinoma-derived cell population (IC-12) undergoes dramatic changes in morphology, and the anchorage-independent growth of these cells is inhibited. This phenomenon is termed normalization. The strategy adopted for elucidating the cellular/molecular changes associated with the induction of these phenotypic alterations was to define the differences in mRNA expression patterns between IC-12 populations exhibiting the neoplastic phenotype (wild-type cells) and those exhibiting the normalized phenotype. For this purpose, the differential display technique and subsequent Northern blot analyses were used. Once specific, differentially expressed genes were identified, the temporal sequence of altered gene expression was determined by monitoring the levels of mRNA expression after the addition of normal cell-conditioned medium. Some of the identified known genes are grouped into three general categories: (a) group I genes are those involved in cellular adhesion processes; (b) group II genes are those involved in signal transduction pathways; and (c) group III genes are those involved in transcriptional and translational processes. Genes that are differentially expressed during the normalization process seemed to exhibit characteristic temporal expression patterns after the addition of normal cell-conditioned medium. Identification of these differentially expressed genes and their associated cellular functions provide insight into some of those regulatory pathways in neoplastic cells that are amenable to regulation by normal cells. An analysis of the temporal sequence of altered gene expression provides further information that allows the identification of those genes that are likely to be critical upstream effectors regulating transcriptional regulatory events that result in the moderation of neoplastic behavior.

Multiple hepatoblastomas associated with trisomy 18 in a 3-year-old girl.

A very rare case of full trisomy 18 associated with multiple hepatoblastomas is reported. The patient also had ventricular septal defect and patent ductus arteriosus, which were repaired at 6 months of age. After the cardiac surgery, she was noted to have an abdominal mass and an elevated serum alpha-fetoprotein level. A partial hepatic lobectomy was performed at 7 months of age, and the resected tumor was diagnosed as a fetal-type hepatoblastoma. At 2 years and 4 months of age, a chest radiography disclosed an elevated left diaphragm, and abdominal ultrasonography demonstrated a tumor in the left hepatic lobe. The resected tumor was also diagnosed as a fetal-type hepatoblastoma. Chromosomal analysis demonstrated that the karyotypes of peripheral blood and hepatic tumor cell obtained on two occasions were both 47,XX, +18. She has no evidence of recurrence at 3 years of age without specific therapy.

[Molecular-biological aspects of juvenile respiratory papillomatosis and its combined treatment]. / Molekuliarno-biologicheskie aspekty iuvenil'nogo respiratorno papillomatoza i ego kombinirovannoe lechenie.

Systemic clinical and molecular-biological analyses of cause-effect relations between human papillomatosis virus (HPV) and juvenile respiratory papillomatosis (JRP) disclosed general mechanism of HPV infection initiation and stages of tumor genesis. However, there is no consent on the universal etiopathogenetic approach to the disease treatment. The authors give some results to the disease treatment. The authors give some results of present-day combined treatment of JRP which includes surgical removal of papillomas and modulation of immunity by interferon preparations.

The uteroglobin promoter targets expression of the SV40 T antigen to a variety of secretory epithelial cells in transgenic mice.

Adenocarcinomas derived from the lining epithelia of various organs are the most common malignant tumors in human pathology and about 50% are hormone dependent. The tissue-specific and hormally regulated expression of the rabbit uteroglobin gene is secretory epithelial cells could provide a means of establishing in vivo models for a variety of human tumors originating from such tissues. We have generated trangenic mice inheriting a hybrid gene containing 4.7 kb of the rabbit uteroglobin 5'-flanking sequences fused to the SV40 T antigen encoding region. All transgenic founders examined exhibited bronchio-alveolar adenocarcinomas, probably due to expression of the transgene in Clara cells. Most founders also developed tumors of the submandibular salivary gland, and adenocarcinomas of the stomach. Adenocarcinomas and dysplasias in epithelial cells of the male and female genital tract were found in single founders. Immunohistochemical analysis showed that T antigen expression interfered with stable maintenance of the differentiated phenotype as documented by expression of the endogenous uteroglobin gene. One founder gave rise to a mouse line, UT7.1. Transgenic descendants of UT7.1 developed lung adenocarcinomas and, depending on the genetic background, exhibited tumors of the stomach, the salivary gland and the pancreas. Sporadically male descendants developed prostatic adenocarcinoma whereas females developed dysplasias and adenocarcinomas of the uterus and the oviduct. Thus, the UT7.1 mouse line could be a useful model for several epithelial neoplasias.

Regulation of normal and transformed tracheobronchial epithelial cell proliferation by autocrine growth factors.

Several peptide growth factors have been identified as autocrine regulators of normal tracheobronchial epithelial cells, including the transforming growth factors alpha and beta. Using in vitro tissue culture models of multistep neoplastic transformation as well as cell lines derived from human bronchogenic tumors, a significant number of growth factors have been found to function as autocrine factors for neoplastic tracheobronchial cells as well. In several instances, the regulation of the autocrine pathway is disrupted in neoplastic tracheobroncial cells compared with their normal counterparts. These results indicate that there are multiple aberrations in growth factor pathways occurring in tracheobronchial epithelial cells during progression to the neoplastic phenotype.