Case Lymphoepithelioma-like of the Report Hidenobu Takahashi, MD, PhD,1,2 Masahiko Harada, MD, PhD,1,2 Tetsushi Ito, MD, PhD,1,2 and Harubumi Kato, MD, PhD2

Lymphoepithelioma is a lymphocyte-rich, poorly differentiated and non-keratinizing of the nasopharynx. Tumors arising outside the nasopharynx are rare and are designated as lymphoepithelioma-like (LELCs). This is the third reported case of LELC of the trachea. A 27-year-old woman was referred to our hospital on suspicion of bron- chial asthma on August 2000. A polypoid tumor of the cervical trachea was recognized on neck X-ray, neck computed tomography (CT) scan, and fiberoptic bronchoscopy. The protruding tumor was resected endoscopically by an electrosurgical snare. Histological and immunohis- tochemical examinations demonstrated large irregular polygonal cells extending in an islet or trabecular pattern among lymphoid stroma. These polygonal cells showed non-keratinization, atypia and prominent nucleoli. In situ hybridization showed these cells were infected with the Epstein-Barr (EB) virus. The infiltrating lymphocytes consisted of both T- and B-lymphocytes with no atypia. Thus the tumor was diagnosed as LELC. Blood examination revealed a past EB viral infection. Sphenoid resection of the tracheal cartilaginous portion was performed for re- sidual tumor. We gave 50 Gy postoperative radiation, and she has been disease free in the 6-year follow-up period. (Ann Thorac Cardiovasc Surg 2007; 13: 191–194)

Key words: lymphoepithelioma-like carcinoma, trachea, electrosurgical snare, Epstein-Barr virus

Introduction Case

Lymphoepithelioma is a lymphocyte-rich, poorly differ- In August 2000, a 27-year-old woman consulted her doc- entiated and non-keratinizing squamous cell carcinoma tor because of discomfort in the larynx and stridor since of the nasopharynx.1) Tumors arising outside the nasophar- April that year. She came to the department of internal ynx are rare and are designated as lymphoepithelioma- medicine of our hospital on suspicion of asthma in the like carcinomas (LELCs).2) The pathogenesis of LELCs same month. Chest and neck X-ray suggested a tracheal is still unknown. While many LELCs related to Epstein- tumor (Fig. 1, A–C). On the same day, laryngoscopy Barr (EB) viral infection have been proved by in situ hy- showed a tumor in the trachea. Neck computed tomogra- bridization, some cases had no relation to EB virus. At phy (CT) films showed the tumor was protruding from present, only two cases of LELC of the trachea have been anterior wall of the trachea causing airway stenosis (Fig. reported in the English language literature.3,4) 2A). Tumor invasion to extra-tracheal tissues nor swell- ing of lymph nodes could be seen. Fiberoptic bronchoscopic findings revealed the poly- From 1Department of Surgery, Tokyo Metropolitan Health and poid tumor protruded into the tracheal lumen from the Medical Treatment Corporation Ebara Hospital, Tokyo, and 2First Department of Surgery, Tokyo Medical University, Tokyo, Japan cartilaginous portion of the cervical trachea. It appeared granulous and likely to bleed easily (Fig. 2B). Definitive Received January 29, 2007; accepted for publication February 4, diagnosis could not be obtained despite transbronchial 2007 biopsy. She was admitted to our hospital for diagnosis Address reprint requests to Hidenobu Takahashi, MD, PhD: Respiratory Center, Tokyo Medical University Hachioji Medical and therapy on September 2000. Most of the protruding Center, 1163 Tatemachi, Hachioji, Tokyo 193–0998, Japan. tumor was resected endoscopically using a electrosurgical

Ann Thorac Cardiovasc Surg Vol. 13, No. 3 (2007) 191 Takahashi et al.

Fig. 1. A, B: It was very difficult to determine the tracheal tumor on these chest X-ray films. C: Neck X-ray clearly shows the tracheal tumor (arrow).

Fig. 2. A: Neck computed tomography (CT) showed the tumor was protruding from the anterior wall of the trachea causing airway stenosis. Neither tumor invasion to extra-tracheal tissues nor swelling of lymph nodes could be seen. B: Fiberoptic bronchoscopic findings revealed the polypoid tumor protruded into tracheal lumen from the cartilaginous portion of the cervical trachea. It appeared granulous and likely to bleed easily C: Most of the protruding tumor was resected fiberoptic bronchoscopically by an electrosurgical snare. The resected tumor was 18×13×13 mm, granulous, smooth, orange and elastic hard. snare (Fig. 2C). She was discharged the next day with no pattern among lymphoid stroma. No keratinization could complications or bleeding. Her symptoms had resolved. be seen in the tumor. The polygonal cells showed atypia Histologically, the surface of the tumor was covered and prominent nucleoli (Fig. 3B). In situ hybridization by ciliated columnar mucosa (Fig. 3A). The tumor con- revealed the EB virus. Immunohistochemical examina- sisted of small mature lymphocytic nests with large ir- tions revealed that the infiltrating cells were both T- and regular polygonal cells extended in an islet or trabecular B-lymphocytes with no atypia. From these findings, lym-

192 Ann Thorac Cardiovasc Surg Vol. 13, No. 3 (2007) Lymphoepithelioma-like Carcinoma of the Trachea

Fig. 3. A: Histologically, the surface of the tumor was covered by ciliated columnar mucosa. B: The tumor consisted of small mature lymphocytic nests with large irregular polygonal cells extended in an islet or trabecular pattern among lymphoid stroma. The polygonal cells showed atypia and prominent nucleoli.

phoepithelioma-like tumor of trachea was diagnosed. the tracheal mucosa and the surgical margin was nega- Tumor markers, CEA, CA19-9, SCC, SLX and Pro- tive. She was discharged on the 16th postoperative day GRP values were all within normal limits. Her history of with no postoperative complications. We gave 50 Gy of EB viral infection was revealed as EB-IgG 320, EB-IgM adjuvant radiotherapy to the cervix and upper mediasti- <10, EB-IgA 10 and EBNA 20. Additional excision was nal region. No recurrence or metastasis has been found thought necessary, because the tumor remained. Before on follow-up for 6 years by systemic CT scan and operation, fiberoptic bronchoscopic findings showed fiberoptic bronchoscopy (Fig. 4B). slight irregularity of tracheal mucosa at the stalk of the tumor (Fig. 4A). Discussion

Treatment Lymphoepithelioma was first reported by Schmincke in 1921.1) Lymphoepithelioma is a lymphocyte-rich, poorly A sphenoid resection of the cartilaginous portion of the differentiated and non-keratinizing squamous cell carci- trachea was performed in November 2000 under general noma of the nasopharynx with distinctive clinical, epi- anesthesia using a laryngeal mask. The cervical trachea demiologic and etiologic features. Histologically and was exposed sufficiently by ablating surrounding tissues immunophenotypically identical tumors arising outside via a neck collar incision. The isthmus of the thyroid gland the nasopharynx are designated as LELCs.2) Details of was removed and the bilateral recurrent nerves were pre- LELCs have been reported in foregut-derived organs such served carefully. The tumor could not be seen from the as the lungs, gastrointestinal tract, salivary glands, thy- operative field, thus the range of resection of the trachea mus and so on. Nasopharyngeal lymphoepithelioma and was decided on fiberoptic bronchoscopic findings during LELCs are similar, but there is some evidences that they operation to leave a tumor margin of more than 5 mm. are etiologically distinct. Serological studies and molecu- Finally, three rings of tracheal cartilaginous portion (1.3 lar techniques have consistently demonstrated an cm) were resected. The membranous portion of the tra- etiopathologic association between EB virus and lym- chea was preserved, because no abnormality was found phoepithelioma and LELC of several locations. Lymphoep- at all. Swollen regional lymph nodes were not detected. ithelioma patients are more common in Southeast Asian Pathological examinations of the polypectomy speci- people including Chinese, suggesting the presence of men indicated a residual tumor. Following the tracheo- some ethnic differences.4,5) procedure the tumor invasion was found to be limited to EB viral infection was not described in the first case

Ann Thorac Cardiovasc Surg Vol. 13, No. 3 (2007) 193 Takahashi et al.

Fig. 4. A: Fiberoptic bronchoscopic findings before operation showed slight irregularity of tracheal mucosa at the stalk of the tumor (arrow). B: Fiberoptic bronchoscopic findings 6 years after surgery showed only a little scar formation at the resected site.

but was demonstrated in the second case report. In our References case, EB virus related LELC of the trachea was revealed because titers of the antibody to EB virus were elevated 1. Schmincke A. Uber lymphoepitheliale Geschwulste. in the sera and in situ hybridization of the tumor demon- Pathl Anat 1921; 68: 161–70. 2. Iezzoni JC, Gaffey MJ, Weiss LM. The role of Epstein- strated the presence of EB virus. Barr virus in lymphoepithelioma-like carcinomas. Am Tracheobronchial tumors often cause asthma-like J Clin Pathol 1995; 103: 308–15. symptoms. We should remember EB viral infection rarely 3. Onizuka M, Doi M, Mitsui K, Ogata T, Hori M. Undif- causes lymphoepithelioma and/or LELCs in certain re- ferentiated carcinoma with prominent lymphocytic in- gions including the trachea. filtration (so-called lymphoepithelioma) in the trachea. Chest 1990; 98: 236–7. We resected most of the protruding tumor using an 4. Satyanrayana S, Pathak SD, Saraswat V, Sarma YS, endoscopic electrosurgical snare. This method is very use- Bharadwaj R, Goorha YK. Tracheal lymphoepithe- ful and safe for such protruding tracheal tumors and to lioma-like carcinoma: a case report. Indian J obtain material for pathological diagnosis.6) 2002; 39: 112–5. Since lymphoepitheliomas and LELCs are usually ra- 5. Han AJ, Xiong M, Zong YS. Association of Epstein- diosensitive, we gave 50 Gy of postoperative radiation to Barr virus with lymphoepithelioma-like carcinoma of 7) the lung in southern China. Am J Clin Pathol 2000; the cervix and upper mediastinal region. She was suc- 114: 220–6. cessfully treated, and is disease free after more than 6 6. Sagawa M, Sato M, Takahashi H, Minowa M, Saito years but further follow-up is necessary. To our knowl- Y, Fujimura S. Electrosurgery with a fiberoptic bron- edge, there are only two reports of LELC of the trachea choscope and a snare for endotracheal/endobronchial in the English literature. This is the third case. tumors. J Thorac Cardiovasc Surg 1998; 116: 177–9. 7. Chen FF, Yan JJ, Lai WW, Jin YT, Su IJ. Epstein-Barr virus-associated nonsmall cell lung carcinoma: undif- Acknowledgment ferentiated “lymphoepithelioma-like” carcinoma as a distinct entity with better prognosis. Cancer 1998; 82: The authors are indebted to Prof. J. Patrick Barron of the 2334–42. International Medical Communications Center of Tokyo Medical University for his review of this manuscript.

194 Ann Thorac Cardiovasc Surg Vol. 13, No. 3 (2007)