Lymphoepithelioma-like Carcinomas Research Articles

Absence of EBV genome in lymphoepithelioma-like carcinomas of the larynx.

Undifferentiated nasopharyngeal carcinomas are universally associated with Epstein-Barr virus (EBV). This association has been exclusively established in lymphoepithelioma-like carcinomas in some locations. The relationship between EBV and lymphoepithelioma-like carcinomas in the larynx is unknown. In none of the few laryngeal lymphoepithelioma-like carcinomas reported have EBV investigations been carried out. We present here two supraglottic laryngeal lymphoepithelioma-like carcinomas in which EBV antigens were not demonstrable using immunohistochemical and molecular methods. Our results suggest that EBV may not be involved in laryngeal lymphoepithelioma-like carcinoma at least in Western patients.

Immunohistochemical localization of Mcl-1 and bcl-2 proteins in thymic epithelial tumours.

Mcl-1 protein is a new member of the bcl-2 protein family. It is believed to be a blocker of apoptosis but might be different from bcl-2 in the control of apoptosis. Using immunostaining of formalin-fixed, paraffin-embedded sections, we investigated the expression of Mcl-1 in 42 thymic epithelial tumours: three medullary thymomas, five mixed thymomas, seven cortical thymomas, eight well-differentiated thymic carcinomas, 14 squamous cell carcinomas, four lymphoepithelioma-like carcinomas and one undifferentiated carcinoma, bcl-2 immunocytochemical localization was also performed for comparison. High-grade thymic carcinomas, especially squamous cell carcinomas, revealed more intense Mcl-1 immunoreactivity as compared to other subtypes (P < 0.001). In cases that co-expressed Mcl-1 and bcl-2, the less differentiated cells had more intense expression of bcl-2, while the more differentiated cells displayed stronger Mcl-1 immunoreactivity. The differential expression of Mcl-1 and bcl-2 in neoplastic cells provides evidence that these proteins may play different roles in the processes of programmed cell death in thymic neoplasms. The finding that thymic carcinomas have stronger immunoreactivity for Mcl-1 indicates that this protein could be a useful marker to differentiate aggressive thymic epithelial tumours from indolent ones.

Absence of Epstein-Barr virus in lymphoepitheliomalike carcinoma of the skin. Polymerase chain reaction evidence and review of five cases.

Lymphoepithelioma is a lymphocyte-rich, poorly differentiated, nonkeratinizing carcinoma of the nasopharynx with distinctive clinical, epidemiologic, and etiologic features. Histologically and immunophenotypically identical tumors arising outside the nasopharynx are designated lymphoepitheliomalike carcinomas (LELCs), and have been described in the gastrointestinal tract, lung, salivary glands, thymus, and increasingly in the skin. Despite similarities between LELC and nasopharyngeal lymphoepithelioma, there is growing evidence that they are etiologically distinct. Serologic studies and molecular techniques have consistently demonstrated an etiopathologic association between Epstein-Barr virus (EBV) and lymphoepithelioma and LELC of several locations, including stomach, salivary gland, lung, and thymus. Though histologically similar. lymphoepitheliomalike carcinoma of the skin (LELCS) does not contain EBV DNA by RNA in situ hybridization. Recently, techniques for polymerase chain reaction (PCR) using fixed tissue have been described that to our knowledge have not been applied to LELCS. We studied five cases of LELCS, taking advantage of the higher sensitivity of PCR to evaluate the role, if any, of EBV specifically in the pathogenesis of LELCS.

Lymphoepithelioma-like carcinoma of the thyroid gland: Lack of evidence of association with Epstein-Barr virus

Lymphoepithelioma-like carcinomas (LELC) occurring in sites derived from the primitive pharynx and foregut have been reported to show a strong association with Epstein-Barr virus (EBV), especially in the Oriental population. Primary lymphoepithelioma-like carcinoma of the thyroid is an extremely rare neoplasm which has been known under many different names, such as intrathyroidal epithelial thymoma, primary thyroid thymoma, carcinoma of the thyroid showing thymoma-like features, and carcinoma showing thymus-like differentiation (CASTLE). We report one such case in a Chinese woman, whose tumor was negative for EBV by in situ hybridization technique. This finding suggests that LELC of the thyroid may be biologically different from other LELCs, and that detection of EBV may aid in diagnosis when the LELC presents initially in lymph nodes or other metastatic sites.

Expression of epstein-barr virus in carcinomas of major salivary glands: A strong association with lymphoepithelioma-like carcinoma

To elucidate the role of Epstein-Barr virus (EBV) in salivary gland carcinomas, 56 cases of carcinomas of major salivary glands were investigated. These included 14 mucoepidermoid carcinomas, 13 adenoid cystic carcinomas, seven malignant mixed tumors, four adenocarcinomas, four salivary duct carcinomas, two acinic cell carcinomas, two undifferentiated carcinomas without lymphoid stroma, seven lymphoepithelioma-like carcinomas (LELCs), two squamous cell carcinomas, and one small cell carcinoma. EBV transcripts were examined by in situ hybridization using digoxigenin-labeled oligonucleotide antisense probe for EBV-encoded RNA 1 (EBER1) on formalin-fixed paraffin-embedded tissue sections. EBER1 was detected in the malignant epithelial cells in all seven cases of LELC, but not in any of the other carcinomas and the neighboring normal salivary gland tissue. Because all the EBV-negative cases showed satisfactory labeling with the poly d(T) probe, the negative reaction with EBER1 was unlikely to be caused by poor RNA preservation in the tissues. The seven cases of LELC, which were histologically indistinguishable from undifferentiated nasopharyngeal carcinoma (NPC), had a disease-free 4-year survival rate of 85.7%. The results suggest that LELC of the salivary gland in Taiwanese Chinese may share similar EBVrelated pathogenesis with that of NPC.

Epstein-Barr virus latent and replicative gene expression in gastric carcinoma.

Recent reports demonstrated the presence of Epstein-Barr virus (EBV) in about 10% of gastric carcinoma cases, particularly in Asian populations. We carried out a retrospective assessment of the detection rate of EBV gene products in 59 cases of gastric carcinoma of various histological subtypes. In situ hybridization using non-isotopic EBER and BHLF1 oligoprobes, and immunohistochemistry using antibodies to latent membrane protein 1 (LMP-1) were applied to paraffin-embedded sections. Tumour cells in five out of 59 cases (8.5%) were found to be EBER positive by in situ hybridization, but no staining was observed with LMP-1 antibodies. Four EBER positive cases were lymphoepithelioma-like carcinomas and one case was a well differentiated adenocarcinoma, suggesting a stronger association with the former subtype. Among the four EBER positive lymphoepithelioma-like carcinomas, BHLF1 transcripts were expressed in one case in a few tumour cells, indicating the possible activation of a lytic cycle. In nine cases (including three EBER positive cases) a few scattered EBV-infected lymphocytes were seen in the normal mucosa but we were unable to detect any EBER positive normal epithelial cells. Our results show that, in a French population, the incidence of EBV-associated gastric carcinoma is similar to that in other geographic areas. The clinical implications of these findings, however, remain unclear.

Epstein-barr virus is detected in undifferentiated nasopharyngeal carcinoma but not in lymphoepitheliomalike carcinoma of the urinary bladder

The Epstein-Barr virus (EBV) is associated with nasopharyngeal carcinoma (NPC) and with lymphoepithelioma-like carcinomas developing in certain anatomic sites. In this study, an in situ hybridization was used to identify EBV-encoded ribonucleic acid (RNA) (EBER1) transcripts in 32 of 45 cases of NPC but not in any of the 11 lymphoepithelioma-like carcinomas developing in the urinary bladder. EBER1 was most commonly detected in those NPCs having undifferentiated or nonkeratinizing squamous histology rather than the keratinizing squamous cell subtype of NPC. The EBV-encoded latent membrane protein 1 (LMP1) was expressed focally in only seven of 21 EBER1-positive NPCs by an immunohistochemical technique. These findings imply that EBER1 hybridization is more sensitive than LMP1 immunohistochemistry on paraffin sections in detecting carcinoma-associated virus. Previous in vitro studies have suggested that LMP1 expression might be a function of differentiation, but this study of naturally infected NPCs showed no strong correlation between LMP1 positivity and degree of tumor differentiation, albeit a limited spectrum of differentiation that could be examined. In two cases in which frozen tissue was available, the NPCs were monoclonal with respect to viral DNA structure, implying that the virus was present before malignant transformation. Unlike NPCs, the lymphoepithelioma-like carcinomas of the bladder were uniformly EBV negative, lending further evidence to the growing body of literature linking EBV with lymphoepithelial carcinomas of foregut-derived tissues but not with similar-appearing tumors developing in other anatomic sites.

In situ detection of Epstein–Barr virus in non‐small cell lung carcinomas

Epstein-Barr virus (EBV) is strongly associated with nasopharyngeal carcinoma and lymphoepithelioma-like carcinomas (LELC) of foregut-derived organs. Recently this group of EBV-associated carcinomas has been expanded by the identification of the virus in conventional adenocarcinomas of the stomach. In situ hybridization (ISH) using a sensitive digoxigenin-labelled EBER RNA probe was performed on 167 consecutive unselected primary non-small cell lung carcinomas, to determine the frequency of EBV association in these tumours. Nine cases (5.4 per cent) showed strong EBER signals in the tumour cell nuclei. By immunohistochemistry, four of the EBER-positive tumours showed patchy expression of the viral latent membrane protein (LMP-1) and none showed any expression of the EBV nuclear antigen 2 (EBNA2). Morphologically, all the positive tumours were LELC, whereas no conventional type of non-small cell lung carcinoma showed EBV association. The LELC presented a morphological spectrum from undifferentiated to squamoid or glandular differentiation. The patients showed a male to female ratio of 8:1. The mean age at presentation was 48 years. Smoking was not a risk factor. All patients were alive at follow-up periods of 23-52 months. Southern blot analysis performed on eight of the nine positive tumours showed a clonal episomal form of EBV, suggesting the clonal expansion of an infected tumour cell early in oncogenesis. These characteristics of the EBV-associated lung tumours justify their consideration as a distinct clinicopathological entity.

PRESENCE OF EPSTEIN-BARR-VIRUS IN BREAST-CARCINOMA

Epstein-Barr virus (EBV) is associated with human B cell lymphomas, but is also commonly found in the epithelial cells of undifferentiated nasopharyngeal carcinoma. As recent reports have also suggested a wider distribution particularly in lymphoepithelioma-like carcinomas, we investigated its presence in breast carcinomas of varying histology. Using PCR amplification of DNA extracted from paraffin sections, we found that EBV was present in 15/28 breast cancers. It seemed to be more prevalent in Paget's disease and in medullary carcinomas and less frequent in the invasive ductal cancers that constitute about 75% of breast carcinomas. This was confirmed by analysis of purified DNA extracted from a further 48 invasive ductal carcinomas: 19 were EBV positive. Latent membrane viral protein was detected by immunohistology in scattered epithelial tumour cells. The vast majority of lymphoid cells were unstained. A rough approximation indicates that there could be up to several hundred copies of the EBV genome per mu g of extracted tissue DNA. We were unable to demonstrate the presence of RNA by in situ hybridisation using fluorescein labeled EBER oligonucleotides but this may be due to technical reasons. No EBV DNA was found using PCR in the 12 normal breast specimens examined. These initial results suggest that the EBV genome is present in certain breast epithelial malignancies.

Absence of Epstein-Barr virus in medullary carcinoma of the breast as demonstrated by immunophenotyping, in situ hybridization and polymerase chain reaction.

Medullary carcinoma of the breast is an epithelial malignant proliferation that shares many characteristics (macroscopic, microscopic, epidemiologic, and prognostic) with lymphoepithelioma-like carcinomas of various sites. The authors hypothesized that they could also share the same etiologic agent, the Epstein-Barr virus (EBV). Epstein-Barr virus, a virus of the herpesvirus family, is to be associated with lymphoepithelioma-like carcinomas of the nasopharynx, stomach, lung, thymus, and salivary gland. Therefore, the authors looked for the virus in a series of 10 medullary carcinomas of the breast. Using immunohistochemistry, in situ hybridization and polymerase chain reaction, this investigation failed to show evidence of EBV. Similar negative results have been reported in lymphoepithelioma-like carcinomas arising in the skin and in the uterine cervix, which like the breast do not originate in the foregut. These results suggest that the pathogenesis of these tumors is not unique, implicating probably different etiopathogenic entities.

The role of Epstein-Barr virus in lymphoepithelioma-like carcinomas.

Epstein-Barr virus (EBV) has been implicated in the pathogenesis of a variety of lymphoproliferative disorders and several epithelial neoplasms, including undifferentiated nasopharyngeal carcinoma (UNPC; lymphoepithelioma). Lymphoepithelioma-like carcinomas (LEC) are tumors with morphologic features identical to UNPC that occur outside the nasopharynx. To determine whether EBV is associated with LEC, the authors conducted a comprehensive literature review of all pathologically documented LEC reported to date in the English literature. In summary, EBV is associated consistently with LEC from only four anatomic sites: stomach, salivary gland, lung, and thymus. Racial and/or geographic factors influence the association of EBV with LEC in some of these organs. Specifically, the association of EBV with LEC of the salivary gland and lung is restricted to Asian patients, whereas the association of EBV with gastric and thymic LEC is independent of race. The presence or absence of EBV in LEC does not appear to be prognotically important in those cases studies to date.

In Situ Detection of Epstein-Barr Virus in Gastric and Colorectal Adenocarcinomas

The association of Epstein-Barr virus (EBV) with lymphoepithelioma-like carcinoma in the nasopharynx, which is common in Chinese from the southern region, is well established. Recently, EBV has also been found to be associated with lymphoepithelioma-like carcinomas (LELCs) and carcinomas with prominent lymphoid infiltrates in the stomach. We investigated for the presence of EBV in 74 cases of gastric adenocarcinoma and 36 cases of colorectal adenocarcinoma from Chinese patients by in situ hybridization (ISH) using an antisense EBER probe. In seven cases (9.5%) of gastric carcinoma, EBER was highly expressed in the adenocarcinoma cells and metastatic tumor cells in regional lymph nodes. In all these cases, the normal gastric epithelium was EBV negative. None of the colorectal carcinomas showed a positive signal. Isolated positive lymphoid cells were frequently found in both tumors. Of the seven positive cases, only one was LELC, and the others were conventional adenocarcinomas of the intestinal type. Five showed expression of the viral RNA in all tumor cells as well as the surrounding dysplastic epithelium. Interestingly, the sixth case showed distinct negative islands of dysplastic glands adjacent to strongly positive dysplastic glands and invasive carcinoma cells. This pattern of positivity, together with negative normal gastric epithelium and positive metastatic tumor, suggested that EBV infection occurred in the dysplastic phase and that an apparent growth advantage was conferred by the EBV infection.

Gastric carcinoma: monoclonal epithelial malignant cells expressing Epstein-Barr virus latent infection protein.

In 1000 primary gastric carcinomas, 70 (7.0%) contained Epstein-Barr virus (EBV) genomic sequences detected by PCR and Southern blots. The positive tumors comprised 8 of 9 (89%) undifferentiated lymphoepithelioma-like carcinomas, 27 of 476 (5.7%) poorly differentiated adenocarcinomas, and 35 of 515 (6.8%) moderately to well-differentiated adenocarcinomas. In situ EBV-encoded small RNA 1 hybridization and hematoxylin/eosin staining in adjacent sections showed that the EBV was present in every carcinoma cell but was not significantly present in lymphoid stroma and in normal mucosa. Two-color immunofluorescence and hematoxylin/eosin staining in parallel sections revealed that every keratin-positive epithelial malignant cell expressed EBV-determined nuclear antigen 1 (EBNA1) but did not significantly express CD45+ infiltrating leukocytes. A single fused terminal fragment was detected in each of the EBNA1-expressing tumors, thereby suggesting that the EBV-carrying gastric carcinomas represent clonal proliferation of cells infected with EBV. The carcinoma cells had exclusively EBNA1 but not EBNA2, -3A, -3B, and -3C; leader protein; and latent membrane protein 1 because of methylation. The patients with EBV-carrying gastric carcinoma had elevated serum EBV-specific antibodies. The EBV-specific cellular immunity was not significantly reduced; however, the cytotoxic T-cell target antigens were not expressed. These findings strongly suggest a causal relation between a significant proportion of gastric carcinoma and EBV, and the virus-carrying carcinoma cells may evade immune surveillance.

Lack of Evidence of Pathogenetic Role of Epstein-Barr Virus in Thymic Lymphoid Hyperplasia and Thymomas in the Chinese Population of Hong Kong

A previous study from Hong Kong by McGuire et al. reported frequent demonstration of Epstein-Barr virus (EBV) DNA by Southern blot analysis in thymoma, thymic lymphoepithelioma-like carcinoma, and thymic lymphoid hyperplasia. This provoca tive finding, however, could not be confirmed by studies in the Western populations using the Southern blot technique and/or polymerase chain reaction to detect EBV- DNA or in situ hybridization to detect EBV encoded RNA (EBER), raising the possibility that the association with EBV may be restricted to Asians. This study was performed to clarify this issue by using a highly sensitive localization technique for EBER on a larger series from the Asian population of Hong Kong. Paraffin sections obtained from 10 cases of thymic lymphoid hyperplasia, 42 noninvasive thymomas (including one case previously reported to be EBV positive), 11 invasive thymomas, and 9 thymic carcinomas (including 5 cases of lymphoepithelioma-like carcinoma) were studied. EBER signal was not detected in the epithelial cells in any of the cases except for two cases of lymphoepithelioma-like carcinoma. In two thymomas, a few small lympho cytes (&lt;0.1%) were EBER positive. Failure to detect EBER was not an artifact due to RNA denaturation, because preserved mRNA could be demonstrated by oligo-dT labelling in 56 of the 72 cases. Thus, the results of this study on Hong Kong Chinese are in keeping with those reported in Caucasians, and more recently in Japanese and Taiwan Chinese, in that there is no association of EBV with thymic lymphoid hyperpla sia or thymoma, and that EBV may be demonstrated in a proportion of thymic lymph oepithelioma-like carcinomas. The positive results previously reported cannot be ex plained, because the occasional EBV-carrying lymphocytes detected in rare cases of thymoma should be insufficient to give a positive EBV result by Southern blot tech nique. Int J Surg Pathol 2(1):17-22, 1994

Clonal Epstein-Barr virus in lymphoepithelioma-like carcinoma of the lung.

Lymphoepithelioma of the nasopharynx is an undifferentiated carcinoma with a prominent lymphoid infiltrate. A consistent association with Epstein-Barr virus (EBV) has been demonstrated over the years by a variety of methods. More recently, undifferentiated carcinomas with a similar morphology have been described in other anatomical locations, often of foregut origin. However, for lymphoepithelioma-like carcinoma, the association with EBV has been more tenuous, especially in Western countries. Interestingly, these tumors have shown a geographic distribution similar to nasopharyngeal lymphoepithelioma, with relatively high frequency of EBV positive cases in Asian patients. We report five cases of lymphoepithelioma-like carcinoma arising in the lung. In situ hybridization revealed the presence of EBV in all cases with localization to the epithelial cells only. Southern-blot analysis from two cases revealed the presence of clonal episomal EBV in the tumor tissue. These findings further support the hypothesis that EBV is also associated with lymphoepithelioma-like lung carcinomas and suggest that EBV infection has preceded the clonal expansion of the tumor.

Study of Epstein-Barr virus early RNA1 (EBER1) expression by in situ hybridization in thymic epithelial tumors of Chinese patients in Taiwan

Forty-one thymic epithelial tumors from Chinese patients in Taiwan, including 14 noninvasive thymomas, seven invasive thymomas, and 20 thymic carcinomas, were investigated for the presence of Epstein-Barr virus transcripts by in situ hybridization using digoxigenin-labeled riboprobes for EBER1 expression. None of the 14 noninvasive thymomas or seven invasive thymomas had detectable EBER1. Only one of 20 thymic carcinomas was positive for EBER1. This positive tumor was a lymphoepithelioma-like carcinoma found in a 19-year-old patient. Four different cases of lymphoepithelioma-like carcinoma were negative. Of note, the present case and all previously reported cases of Epstein-Barr virus-associated thymic carcinomas were lymphoepithelioma-like carcinomas. These results are consistent with those of several Western studies and do not support the view that there are geographic or racial differences affecting the role of Epstein-Barr virus in the pathogenesis of thymic epithelial tumors.

Lymphoepitheliomalike Carcinoma of the Skin

Lymphoepithelioma is a malignant epithelial neoplasm of the nasopharynx. Similar malignancies--lymphoepitheliomalike carcinomas--of salivary glands, thymus, larynx, lung, stomach, and uterus have been described. We present here a case of lymphoepitheliomalike carcinoma of the skin in an 84-year-old woman. Histologically this neoplasm presented as a fairly discrete dermal aggregate of syncytial nests of epithelioid-appearing cells that displayed no squamous or glandular differentiation, surrounded by a dense lymphocytic infiltrate. Results of immunophenotypic studies showed expression of high molecular weight cytokeratins and increased density of dermal dendrocytes within and adjacent to the tumor. No Epstein-Barr viral genomic sequences were detected by in situ hybridization, which suggests that cutaneous neoplasms may have different etiologic agents compared with similar tumors, found to be associated with this DNA-containing virus, arising in extracutaneous sites. The combined light microscopic and immunohistochemical assessment of this rate cutaneous neoplasm permits distinction of lymphoepitheliomalike carcinoma from benign/malignant lymphoproliferative disorders or neuroendocrine carcinomas.

Poorly differentiated adenocarcinoma with lymphoid stroma (lymphoepithelioma-like carcinomas) of the stomach. Report of three cases with Epstein-Barr virus genome demonstrated by the polymerase chain reaction.

Lymphoepithelioma of the nasopharynx is an undifferentiated carcinoma with prominent lymphoid infiltration. Histologically similar tumors have been documented in the skin, lung, thymus, salivary gland, tonsil, and uterine cervix. The authors report three cases of gastric carcinoma that were histologically and immunohistochemically similar to lymphoepithelioma. The patients were elderly white persons (61, 76, and 77 years of age); two of them had previous partial gastric resections for benign ulcer disease. The tumors were located on the lesser gastric curvature (two cases) and at a previous anastomotic site (one case) and measured 3, 4, and 7 cm in largest dimension. Grossly, each neoplasm was a raised plaque-like lesion with a central ulcer. Microscopically, all three tumors were similar, with poorly differentiated polygonal tumor cells scattered throughout a dense lymphocytic background. In a few areas, tumor cells formed ill-defined cords. In two cases, the neoplasms invaded the gastric muscle layer but had a well-delineated (pushing) margin. The tumor cells were immunohistochemically positive for AE3-defined keratin, confirming their epithelial nature. The lymphocytes were a mixture of UCHL-1-positive T cells and L-26-positive B cells. Portions of the Epstein-Barr virus genome were present in all cases, as detected by the polymerase chain reaction. The morphologic features of these cases are similar to those of lymphoepithelioma in other anatomic sites, and these tumors represent a unique subtype of gastric carcinoma.

Thymic carcinoma

Among 54 mediastinal tumours we examined in the past 20 years, there were 5 cases of primary thymic carcinomas, each with widespread metastases. Histological features in three cases were consistent with lymphoepithelioma-like carcinoma. One case showed an epidermoid pattern with keratotic pearls resembling Hassall bodies. One undifferentiated carcinoma developed from a cortical thymoma. Epstein-Barr virus could not be detected in tumour tissue with in situ hybridization. A review of the literature revealed only 94 well-documented cases of thymic carcinoma. Both thymic carcinomas and thymomas are neoplasms of the thymic epithelial cells, but thymic carcinomas are obviously histologically malignant and usually not associated with any parathymic syndromes. Epidermoid and lymphoepithelioma-like carcinomas are described along with special forms, such as small- and clear-cell carcinomas, basaloid, sarcomatoid, mucoepidermoid, and adenocystic carcinoma. Compared to the other forms, lymphoepithelioma-like carcinoma has a poor prognosis in regard to metastases and rate of survival. Some thymic carcinomas may develop from pre-existing thymomas.

Malignant cells of epithelial phenotype limited to thoracic lymph nodes

Asymptomatic thoracic lymphadenopathy was incidentally discovered in three patients with no definitive diagnoses. Enlarged lymph nodes, removed at thoracotomy, had irregularly distributed, pleomorphic, malignant-appearing cells. Mitoses were frequent. Electron microscopy showed tonofilament bundles and desmosomes. By immunocytochemistry, these cells uniformly expressed desmoplakin and cytokeratins 8 and 18 and various patterns of coexpression with other cytokeratins. One patient had lymphadenectomy, segmental lung resection and radiotherapy; the second had lymphadenectomy and later a lymphadenectomy with pneumonectomy; and the third had lymphadenectomy and radiotherapy. Neoplastic cells were detected exclusively within thoracic lymph nodes. The patients are well 111, 39 and 13 months after initial presentation. The clinical course and the patterns of intranodal distribution and marker expression of the neoplastic cells are unusual and distinct from most carcinomas metastatic to lymph nodes and reminiscent of “lymphoepithelioma-like carcinomas” described in the thymus and other sites. While the malignant cells may reflect metastases from as yet occult primaries or malignantly transformed ectopic epithelial nests, these tumours may arise by transformation from the cytokeratin-positive “extrafollicular reticulum cells” indigenous to lymphoid organs.