Lymphoepithelioma-like carcinoma of the submandibular salivary gland: a case report

Carcinoma of the salivary gland is an uncommon disease, accounting for less than 1% of all head and neck malignant neoplasm.1 Lymphoepthelioma is a malignant tumor of epithelial origin showing varying amounts of reactive lymphocytic infiltrate. Lymphoepithelioma-like carcinoma (LELC) constitutes a significant proportion of salivary gland carcinoma in Chinese and Eskimo populations and is related to Epstein-Barr virus infection.2,3 Carcinoma of the salivary gland has a propensity for early lymphatic metastasis, and thus a swelling of cervical lymph nodes is occasionally the sole initial symptom. It is very vital to consider a multimodality approach including surgery, radiotherapy and chemotherapy for the treatment in the locally advanced disease. CASE REPORT A 29-year-old woman presented with a history of a mass in right mandible region for more than 1 year without pain, fever, or other symptoms. The contralateral gland was normal. When the mass became increasingly large and firm, she presented to our hospital. Physical examination revealed a firm, mobile and indolent submandibular gland mass, measuring 2.5 cm in diameter. Serum Epstein-Barr virus antibody was negative. Upon excision of right submandibular gland and mass, pathology confirmed diagnosis of LELC of salivary gland, with 2 lymph node metastasis (2+/2). The neoplasm consisted of tumor cells with round and prominent nucleoli. The cell margins were indistinct and the tumor exhibited a syncytial appearance with a marked lymphocytic infiltrate (Fig. 1). The tumor cells expressed cytokeratins (Fig. 2) and were negative for the lymphoid marker (Fig. 3). TNM staging was T2N2bM0 (stage IVA). Fifteen days after her initial excision, she underwent expanded dissection of the right submaxillary triangle and right modified selective neck dissection. Resection of 53 additional lymph nodes revealed no further metastatic cancer. The patient was treated with chemotherapy, which consisting of cisplatin (30 mg/m2, days 1 to 3) and 5-fluorouracil (500 mg/m2, days 1 to 5) every 3 weeks for 2 cycles. She then underwent irradiation to the primary site and upper neck fields to a total dose of 50 Gy at 2 Gy per fraction once a day. Four additional courses of chemotherapy followed the course of radiotherapy, with the same regimen. The patient was alive without recurrence or distant metastasis 16 months after the treatment.Fig. 1.: Operation specimen of submandibular gland showing proliferation of tumor cells with indistinct margins and marked lymphocytic infiltrates (HE, A: original magnification × 100, B: original magnification × 400).Fig. 2.: Immunohistochemical staining of cytokeratin. Cytoplasmic reactions are observed in tumor cells (A: original magnification × 100, B: original magnification × 400).Fig. 3.: Negative immunochistochemical staining of LCA in lymphocytes (original magnification ×400).DISCUSSION Histologically and immunophenotypically identical tumors arising outside the nasopharynx are designated LELCs,4 and have been described in the gastrointestinal tract, lung, salivary glands, thymus, the skin, larynx, thyroid, uterine cervix, prostate, and urinary tract. Indeed, LELCs are characterized by either cohesive nests or by a diffuse growth of malignant epithelial cells in a background of inflammatory cells that are predominantly lymphocytes.5 The cases of LELCs have been conventionally classified as being ‘high grade’ because of their poor histological differentiation. The mainstay of treatment is surgical resection. Despite their poor differentiation and high histological grade, LELCs are very radiosensitive and bear a better prognosis than the other high-grade salivary gland tumors such that radiotherapy has been used instead of surgery as the primary treatment of LELC in some cases.6 Prognosis in this disease depends on the stage7 and grade8,9 of the cancer, the completeness of surgical resection, and when the resection is incomplete, whether or not postoperative radiotherapy is administered.8,10-12 The team of Parsons et al7 and Teo et al13 showed that the best local control was achieved by the combined approach of performing radical resection and then giving radiotherapy. The appearance of LELCs, its clinical course, and behavior were benign in their studies. Postoperative radiotherapy is indicated when the resection margin is positive or close,8 the tumor is high grade,8 there is tumor infiltration of adjacent organs, or regional metastasis is extensive.7 Our patient had 2 regional lymph nodes metastasis for a stage of T2N2bM0, so after operation, we gave her 1 course of radiotherapy and 6 cycles of chemotherapy. LELC in the salivary gland drains primarily to the ipsilateral neck nodes. In contrast, nasopharyngeal carcinoma arises from a midline organ having significant bilateral cervical lymphatic drainage, thus resulting in the frequent occurrence of bilateral nodal disease. Elective radiotherapy to the clinically at-risk neck nodes is indicated for LELC of the head and neck. LELC has been generally considered to be very radiosensitive, and a significant number of gross tumors have been permanently controlled by a radiation dose of 60 Gy.6 It would appear that a dose of at least 50 Gy would be necessary to achieve adequate local control after surgical resection. Hsiung et al14 treated 9 patients with LELC of salivary glands from June 1987 to May 2001. One patient was excluded due to the loss of clinical follow-up after surgery. In the remaining 8 patients, the primary tumor sites were parotid gland (4 patients), submandibular gland (3), and buccal minor salivary gland (1). Seven patients underwent surgical treatment and post-operative radiotherapy, while 1 patient was treated with surgery alone. The survival time ranged from 21.4 months to 145.2 months (mean: 69.1 months, median: 54.5 months). At the end of follow-up, 6 patients were still alive and 2 died. One patient (left submandibular gland, T3N2b) died of distant metastases 21.5 months after the surgical treatment of LELC. The other case (right submandibular gland, T3N0M0) died of intercurrent disease (pontine haemorrhage) 53 months after surgery. No patient suffered local or regional failure after the treatment. Distant failure was noted in 2 patients (left parotid gland T3N2bM0, left submandibular gland, T3N2b) and received chemotherapy with CDDP and 5-fluorouracil. No local or regional failure was noted. The authors advised careful monitoring for distant metastases, especially in patients with more advanced neck node involvement. To address the risk of distant metastases, we treated our patient with 6 cycles of chemotherapy. Cases of relapse may be successfully salvaged by further treatments such as the second operation and radiotherapy. However, it is advisable to carefully treat newly diagnosed patients adjuvantly, as this yields a good prognosis. Acknowledgement: We would like to thank Dr. Case H. Ketting, M.D. (San Jude Hospital, California, USA) for his polishing the English writing of the article.