Brun, Jean-Luc M.D.; Randriambelomanana, Joseph M.D.; Cherier, Lydie M.D.; Lafon, Marie-Edith M.D.; Trufflandier, Nathalie M.D.; Le Bail, Brigitte M.D., Ph.D.
Department of Obstetrics and Gynecology (J-L.B., J.R., L.C.)
Virology Laboratory (J.-L.B., M-E.L.)
Department of Pathology (B.L.), University Hospital Pellegrin
Department of Oncology (N.T.), University Hospital Saint-André, Bordeaux, France
Address correspondence and reprint requests to Jean-Luc Brun, MD, Pôle de gynécologie obstétrique, Hôpital Pellegrin, 33076 Bordeaux Cedex, France. e-mail: firstname.lastname@example.org
Lymphoepithelioma-like carcinoma (LELC), which is commonly reported in the nasopharynx, is a rare condition in gynecology. Its pathogenesis is still unknown. We report a case of LELC of the ovary and review the literature with regard to this histologic pattern among gynecologic malignancies.
An 82-year-old gravida 1, para 1 white woman, postmenopausal for 32 years, with no earlier history of cancer, presented with multiple enlarged left inguinal lymph nodes. Her body mass index was 19. Clinical and biologic investigations were normal, except for an elevated serum CA125 (800 U/mL) level. Ultrasonography and magnetic resonance imaging showed a 9 cm heterogeneous solid pelvic mass close to the uterus. Partial biopsy of the biggest inguinal lymph node (5 cm) showed undifferentiated carcinoma of probable glandular and gynecologic origin based on the presence of hormonal receptors (estrogen+: 80%, moderate intensity, progesterone −: <10%, moderate intensity), cytokeratin (CKAE1/AE3+, CKKL1+, EMA+, CK7+, CK20−, CK19+, CK5/6−, CK34 E12−), and carcinoembryonic antigen positivity labeling. TTF1 and chromogranine A were negative. The epithelial component was composed of poorly differentiated cells arranged in large sheets with no glandular structures. Cells were characterized by large and atypical vesicular nuclei with prominent nucleoli and frequent mitosis. The cytoplasms were eosinophilic and syntycial and devoid of mucosecretion vacuoles. There was a scant fibrous stroma with prominent plasmacytic infiltrate around tumoral sheets. Computerized tomography (CT) and positron emission tomography showed a necrotic pelvic tumor arising from the ovaries and multiple bilateral inguinal and iliac lymphadenomegalies, but no peritoneal carcinomatosis or distant metastasis. A FIGO stage IV ovarian tumor with lymph node involvement was diagnosed and surgery was performed. The diagnostic laparoscopy confirmed a left bulky ovarian tumor without peritoneal carcinomatosis, and the patient was thus considered a good candidate for an optimal debulking surgery. Cytoreductive surgery included total hysterectomy, bilateral salpingo-oophorectomy, total infragastric omentectomy, bilateral inguinal, pelvic, common iliac, and infrarenal para-aortic lymphadenectomy. Cytoreduction was complete. The ovarian tumor measured 10 cm in diameter and appeared as a polycyclic, solid, whitish, firm mass with a central pseudocystic cavity, containing a translucent fluid (Fig. 1). Frozen section analysis confirmed the diagnosis of a poorly differentiated carcinoma. The final histopathologic diagnosis was a mixed poorly differentiated ovarian carcinoma consisting of 95% LELC and 5% moderately differentiated serous adenocarcinoma occupying the whole ovary (Figs. 2, 3). The same aspects as described in the lymph node were observed: syncytial sheets of undifferentiated atypical cells with vesicular nuclei and prominent nucleoli, intermingled with an abundant lymphoplasmacytic stroma. Some highly atypical carcinomatous cells, either giant or multinucleated and pleomorphic, were frequently mixed, whereas more spindle-shaped cells were rare. On occasion, small cytoplasmic mucus droplets were detected by Periodic Acid Schiff and alcian blue. The mitotic index was moderate (5 mitoses/10 high-power fields) and atypical (multipolar) mitosis was frequent. Apoptotis activity was weak and necrotic foci were limited. The immunophenotype of the carcinomatous cells was the same as in the lymph node. In addition, P53 was intensely positive. Immunostaining failed to detect MSH2, MLH1, or MSH6 indicating a lack of microsatellite instability. A minute (<1 cm) subcapsular area showed a more differentiated pattern with cystic and papillary architecture and serous type atypical cells. The lymphoplasmocytic stromal component was abundant and consisted mainly of plasmocytes mixed with variable amounts of small lymphocytes. These cells were visible around, and as infiltrates of, the epithelial nests. The plasma cells were positive with anti-CD138 antibodies (clone MI15, Dako), and polyclonal kappa and lambda light Ig chain expression was found. Lymphocytes were mainly T cells, marked with anti-CD3 antibodies (polyclonal, anti-CD3ε, Dako), mostly of CD4+ type (helper), and CD8+(suppressor) to a lesser degree. Natural killer cells, CD56+ were not detected. B lymphocytes marked with anti-CD20 antibodies were fewer and focally distributed (clone L26, Dako). Epstein-Barr virus (EBV) was screened by immunohistochemistry (anti-LMP1 antibodies, clone CS1-4, Novocastra, and anti-EBNA2 antibodies, clone P2, Menarini), in situ hybridization (Eber Bind HIS probe, Menarini), and real-time polymerase chain reaction. EBV real-time polymerase chain reaction was performed after DNA extraction by amplification of a 169 base-pair fragment in the EBV thymidine kinase-encoding BXLF1 gene with a fluorescence resonance energy transfer-based in house real time method on the LightCycler instrument with the FastStart hybridization kit (Roche Molecular Biochemicals, Indianopolis, IA) (1). None of these 3 techniques detected EBV.
The contralateral ovary, the fallopian tubes, the uterus, the omentum, and the peritoneal fluid were not involved by the tumor. Twenty-eight of the 32 lymph nodes removed were positive for cancer, including 2 with capsule rupture. The tumoral involvement was massive, both in the cortex and medulla, consisting of round syncytial nests of undifferentiated cells getting to confluence and circled by flows of lymphoplasmacytic cells. On occasion, residual follicles were seen under the capsule. They were of hyperplastic appearance with large germinal centers. No peritoneal disease or metastases were found. The postoperative course was uneventful. No adjuvant chemotherapy was administered to the patient because of her advanced age and relatively poor health status (OMS 2). A CT scan 6 months after surgery showed disease recurrence with multiple deep pelvic lymphadenomegalies. Thrombocytopenic purpura had also occurred. However, the patient remained asymptomatic. She was managed by palliative care (corticosteroids) and was still alive at 24 months follow-up.
LELC consists of a proliferation of poorly differentiated epithelial tumor cells with large vesicular nuclei and prominent nucleoli surrounded and infiltrated by dense lymphoplasmocytic infiltrates, mainly T lymphocytes. This tumor is a distinctive subtype of nasopharyngeal carcinoma, but may also affect other organs such as the salivary gland, thymus, lungs, and skin (2). Genital locations are rare, and concern mainly the cervix. To our knowledge, only 1 case of ovarian LELC has been reported earlier in the literature (3).
The clinical histories of our patient and the case reported in the literature bear strong similarities. The case published earlier concerned a 51-year-old postmenopausal woman with an ovarian tumor and massive lymph node involvement including supraclavicular metastasis (3). The CT scan showed a 6 to 8 cm, right ovarian mass, and enlarged conglomerated pelvic and para-aortic lymph nodes. No peritoneal carcinomatosis was found as in our case. Serum CA125 level was elevated to 5850 U/mL. An excisional biopsy of the left supraclavicular lymph node showed the presence of a metastatic carcinoma (undifferentiated tumor cells with enlarged nuclei, vesicular chromatin, and prominent nuclei). On the basis of a clinical diagnosis of ovarian carcinoma with lymph node metastases (FIGO stage IV), the patient underwent 9 cycles of neoadjuvant chemotherapy resulting in the reduction of the ovarian mass, disappearance of lymph node metastases, and normalization of the serum CA125 level. The patient was kept on expectant management for 1 year. Standard interval surgery was then performed because of a slight increase of CA125 to 69 U/mL. A multinodular solid tumor of 4 cm with intervening fibrous septa was removed. There was no pseudocystic cavity as in our case. Microscopically, the nodules were composed of cohesive sheets of large epithelioid cells, sometimes pleomorphic and hyperchromatic, admixed with an intense lymphoplasmacytic infiltrate and some lymphoid follicles with germinal centers. We observed the same carcinomatous cells in our case, but plasma cells were more abundant and follicular arrangement was absent. The immunohistochemical profile of this tumor was the same as of our case: CK7+, CK20−, CD3−, and CD20− for the tumor cells; admixture of T cells (CD3+) and B cells (CD20+) with a predominance of T cells for the background lymphoid infiltrate. No information about the presence or not of hormonal receptors was available. EBV was not detected by in situ hybridization. None of the 16 pelvic and para-aortic lymph nodes were involved, and neither was the supraclavicular lymph node, the uterus, or the omentum. The patient did not relapse 28 months after initial diagnosis.
Both tumors exhibited some macroscopic and microscopic differences, which may be explained by the impact of chemotherapy on the tissue architecture, but the morphology of the tumor cells and their immunohistochemical profiles are comparable. In our case, the diagnosis of LELC was retained after first line surgery. Cytoreductive surgery was complete, but the patient relapsed early. One might find it surprising that the patient was still alive after 2 years of follow-up, with only palliative care.
Other gynecologic organs may also be affected by LELC. The cervical location is the most frequent with 48 cases reported in the literature. Cervical LELC have been readily diagnosed at early stages and do not always involve pelvic lymph nodes (4–6). Other locations are rare: 3 endometrial LELC, 2 vaginal LELC, 3 LELC of the vulva, including 1 localized in the Bartholin gland have been reported (7–10). Whatever the location of the tumor, patients with LELC seem to have a better prognosis than patients with conventional carcinomas of the corresponding organs. This may be because of the huge inflammatory host reaction and/or the sensitivity of LELC cells to chemotherapy or radiation therapy.
The pathogenesis of LELC remains unclear. EBV gene sequence findings suggest that EBV infection is a cause for lymphoepithelioma of the nasopharynx and LELC of foregut-derived organs such as the salivary gland, stomach, thymus, and lungs, especially in Asian patients (2). EBV has never been detected in non-foregut–derived organs (kidney, bladder, breast, and liver) and in female genital organs like the endometrium, vagina, or vulva (7–10). The impact of EBV on cervical LELC remains controversial, even in Asian patients. EBV has been found in 11 of 15 cervical LELC from Chinese patients, but not in 12 cervical LELC diagnosed in Japanese and Taiwanese patients (6,11,12). Human papillomavirus (HPV) infection has also been shown to be strongly associated with cervical LELC in 8 of 9 Taiwanese patients and was only detected in 3 of 15 cervical LELC from Chinese patients (6,11). In addition, some cervical LELC reported in the literature either in white or Asian patients were negative for both EBV and HPV (12–14). Thus, organ specificity and geographical or racial factors may be implicated in the relationship between viral infection and LELC. Other pathogenic hypotheses, such as microsatellite instability, may explain the occurrence of LELC because of morphologic similarities with hereditary nonpolyposis colorectal cancer, but our case did not show such a pattern.
Although this condition is rare, gynecology oncologists should consider a diagnosis of LELC of the ovary when a neoplastic pelvic mass is associated with multiple lymphadenomegalies but no peritoneal carcinomatosis. The pathologist should also be aware of this histologic subtype. No firm conclusion about prognosis can be drawn from only 2 case reports. However, this atypical and seemingly aggressive disease might have a relatively good prognosis in contrast to the classic stage III-IV epithelial ovarian tumor. This could possibly be because of the host response to the cancer as shown by a heavy lymphoplasmacytic infiltrate.
The authors thank the Department of Pathology of Haut Leveque University Hospital Bordeaux, France, for their technical assistance.
1. Brengel-Pesce K, Morand P, Schmuck A, et al. Routine use of real-time quantitative PCR for laboratory diagnosis of Epstein-Barr virus infections. J Med Virol 2002;66:360–9
2. Iezzonni J, Gaffey M, Weiss L. The role of Epstein-Barr virus in Lymphoepithelioma-like carcinomas. Am J Clin Pathol 1995;103:308–15
3. Lee S, Park SY, Hong EK, et al. Lymphoepithelioma-like carcinoma of the ovary. A case report and review of the literature. Arch Pathol Lab Med 2007;131:1715–8
4. Bais AG, Kooi S, Teune TM, et al. Lymphoepithelioma-like carcinoma of the uterine cervix: absence of Epstein-Barr virus, but presence of a multiple human papillomavirus infection. Gynecol Oncol 2005;97:716–8
5. Noel J, Lespagnard L, Fayt I, et al. Evidence of human papilloma virus infection but lack of Epstein-Barr virus in Lymphoepithelioma-like carcinoma of uterine cervix: report of two cases and review of the literature. Hum Pathol 2001;32:135–8
6. Chao A, Tsai CN, Hsueh S, et al. Does Epstein-Barr virus play a role in lymphoepithelioma-like carcinoma of the uterine cervix?. Int J Gynecol Pathol 2009;28:279–85
7. Rahimi S, Lena A, Vittori G. Endometrial lymphoepitheliomalike carcinoma: absence of Epstein-Barr virus genomes. Int J Gynecol Cancer 2007;17:532–5
8. McCluggage WG. Lymphoepithelioma-like carcinoma of the vagina. J Clin Pathol 2001;54:964–5
9. Niu W, Heller DS, D'Cruz C. Lymphoepithelioma-like carcinoma of the vulva. J Low Genit Tract Dis 2003;7:184–6
10. Kacerovska D, Nemcova J, Petrik R, et al. Lymphoepithelioma-like carcinoma of the Bartholin gland. Am J Dermatopathol 2008;30:586–9
11. Tseng CJ, Pao CC, Tseng LH, et al. Lymphoepithelioma-like carcinoma of the cervix: association with Epstein-Barr virus and human papillomavirus. Cancer 1997;80:91–7
12. Takai N, Nakamura S, Goto K, et al. Lymphoepithelioma-like carcinoma of the uterine cervix. Arch Gynecol Obstet 2009;280:725–7
13. Kohrenhagen N, Eck M, Höller S, et al. Lymphoepithelioma-like carcinoma of the uterine cervix: absence of Epstein-Barr virus and high-risk human papilloma virus infection. Arch Gynecol Obstet 2008;277:175–8
14. El Hossini Soua A, Trabelsi A, Laarif M, et al. Lymphoepithelioma-like carcinoma of the uterine cervix: case report. J Gynecol Obstet Biol Reprod 2004;33:47–50
Lymphoepithelioma-like carcinoma; Ovarian neoplasms; Immunohistochemistry; Epstein-Barr virus