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Rev Esp Patol 2018;51:18-22 - DOI: 10.1016/j.patol.2017.08.002
Brief report
Lymphoepithelioma-like carcinoma of the large intestine: A case report and literature review
Carcinoma tipo linfoepitelioma de intestino grueso: descripción de un caso y revisión de la literatura
Cristina Díaz del Arcoa,, , Fernando Esteban Collazob, Mª Jesús Fernández Aceñeroa
a Department of Surgical Pathology, Hospital Clínico San Carlos, Madrid, Spain
b Department of General and Gastrointestinal Surgery, Hospital Clínico San Carlos, Madrid, Spain
Recibido 25 abril 2017, Aceptado 18 agosto 2017

Lymphoepithelioma like carcinoma (LELC) is a well-known neoplastic lesion that mainly involves the stomach and which has been linked to Epstein Barr virus infection. There are exceptional cases of intestinal involvement by LELC, with 7 reported cases to date.

We report a new case of LELC affecting the right colon and review the literature on this rare disorder, with special emphasis on pathogenesis, molecular features and differential diagnosis.


El carcinoma tipo linfoepitelioma es una entidad conocida que suele afectar al estómago y se ha relacionado con infección por el virus de Epstein-Barr. La afectación intestinal es mucho más infrecuente, y en la literatura en inglés se han publicado solo 7 casos hasta la fecha.

Describimos un caso de carcinoma tipo linfoepitelioma que afectó al colon derecho y realizamos una revisión de la literatura con especial énfasis en su patogenia, características moleculares y diagnóstico diferencial.

Lymphoepithelioma-like, Carcinoma, Colon, Rectum, Lymphoid
Palabras clave
Linfoepitelioma, Carcinoma, Colon, Recto, Linfocitario

Lymphoepithelial carcinomas (LEC) are undifferentiated carcinomas with a prominent lymphoid stroma. They were reported for the first time in the nasopharynx, where they are associated with Epstein–Barr virus (EBV) infection.1 Lymphoepithelioma-like carcinomas (LELCs) are rare tumors, histologically indistinguishable from undifferentiated nasopharyngeal carcinomas, and they have been reported in salivary glands, thymus, larynx, lung, uterine cervix, urinary bladder and skin.2 In the gastrointestinal tract they have been described in the esophagus, stomach, colon and rectum. We report the eighth case of colonic LELC.

Case description

An 86-year-old woman, with a clinical history of allergy to penicillin and hemolytic anemia due to G6PD deficiency, was diagnosed and treated in 2011 for a low-grade intestinal adenocarcinoma of the usual type affecting the sigmoid colon (pT3 pN0). Four years later a follow-up a colonoscopy revealed an ulcerated infiltrative mass located in the splenic flexure. The biopsy showed a high grade adenocarcinoma with an immunophenotype consistent with an intestinal origin, and the patient underwent a right hemicolectomy. The tumor was ulcerated and measured 4.5×3cm. Light microscopy revealed a solid carcinoma with peri and intratumoral lymphocytes (Fig. 1A and B). The aggregates of tumor cells were broken by the presence of lymphocytes and epithelial cells were polygonal with enlarged nuclei and eosinophilic nucleoli. The inflammatory infiltrate was dense and homogeneous. Immunohistochemistry was performed on formalin fixed sections using CDX2, the four mismatch repair proteins (MLH-1, MSH2, PMS-2 and MSH-6) and LMP-1: CDX2 showed extensive nuclear staining and tumor cells showed loss of expression of MLH1 and PMS2 with preservation of MSH2 and MSH6 (Fig. 2). Subsequent molecular studies revealed a V600E mutation of the BRAF gene. The tumor was microsatellite unstable but due to the V600E mutation detected it was supposed to be sporadic and unrelated to Lynch syndrome. LMP-1 and EBER in situ hybridization were negative. The cancer was staged as a pT3 pN0 (IIA) lesion. The patient developed postoperative paralytic ileus, which responded well to standard conservative management, and a urinary tract infection by Enterococcus faecium with a good response to antibiotics. She was discharged with no further adjuvant therapy, due to the lack of lymph node involvement. 22 months after surgery, she remains well with no evidence of recurrent disease.

Figure 1.

(A) Colorectal lymphoepithelioma-like carcinoma. Nests of malignant epithelial cells with peri and intratumoral lymphocytes (H-E, 100×). (B) Colorectal lymphoepithelioma-like carcinoma. Aggregates of polygonal epithelial cells with enlarged nuclei and eosinophilic nucleoli, broken by the presence of lymphocytes (H-E, 200×). (C) Colorectal medullary carcinoma. Sheets of poorly differentiated carcinoma with intratumoral lymphocytes. Inflammation is mainly peritumoral (H-E, 100×). (D) Colorectal medullary carcinoma. Continuous sheets of malignant epithelial cells, which predominate over lymphocytes (H-E, 200×).

Figure 2.

(A) MSH2 shows positivity in malignant epithelial cells. MSH2, 200×. (B) MSH6 shows positivity in malignant epithelial cells. MSH6, 200×. (C) MLH1 is negative in malignant epithelial cells (lymphocytes are positive). MLH1, 400×. (D) PMS2 is negative in malignant epithelial cells (lymphocytes are positive). PMS2, 400×.


In the gastrointestinal tract, LELCs have been reported in esophagus, stomach, colon and rectum. They are more frequent in the stomach, where approximately 200 cases have been described. We have found only 24 cases in esophagus1 and 7 cases in colon and rectum2–8 in the literature.

The clinical and main pathological features of large intestine tumors are summarized in Table 1, including the present case. Patients’ age ranged from 25 to 86 years (mean: 65.1 years) and there were 4 males and 4 females. 2 patients complained of abdominal pain, 2 had diarrhea or changes in bowel habit, 1 had iron deficiency anemia and in one patient the tumor was an incidental finding. In the case reported by De Petris et al.5 the patient had diarrhea, but we cannot attribute the symptoms to LELC as he had 4 synchronous lesions (the largest being an ulcerated and perforated mucinous adenocarcinoma measuring 8cm). The tumors were widely distributed from the ascending colon to the rectum; the sigmoid colon being the most frequent location. Maximum size ranged from 0.5 to 12cm (mean: 3.8cm). Macroscopically, there were 3 ulcerated infiltrative or stenosing lesions, 2 exophytic polypoid tumors and 2 submucosal lesions. In 6 of them, a preoperative biopsy was performed, but a suspected diagnosis of LELC was made in only 2 cases. EBV was found to be positive in one case and two cases were microsatellite unstable. Most of LELCs were first treated by wedge resection. 3 tumors were stage I and 2 were stage IIA. We have not been able to stage the remaining tumors from the data in the reports. Only one showed lymph node metastases. No recurrences were seen after a mean follow up of 7.6 months.

Table 1.

Clinicopathological features of colorectal LELCs.

Ca  Age
Symptoms  Other findings  Location
Size (mm)
Stage/FUe (months) 
13  77
NS    Transverse colon
Stenosing mass 
24  62
Constipation and left mid-quadrant abdominal pain  Multiple primary benign and malignant tumors. Possible Lynch syndrome  Cecum
Exophytic polypoid mass 
N1. NS/Alive, NPg(12) 
35  44
Abdominal pain and weight loss.
(Synchronic lesions) 
Lynch syndrome (confirmed)
Synchronic mucinous adenocarcinoma 
Right colon
IIA/Alive, NP (7) 
46  72
Diarrhea    Rectum
Central ulceration 
57  25
Follow-up colonoscopy  Ulcerative colitis
Previous adenocarcinomas in rectum and sigmoid colon 
Small submucosal lesion 
NS/Alive, NP (NS) 
68  85
Change in bowel habit    Sigmoid
Sessile polyp 
I/Alive, NP (6) 
72  70
No symptoms. Follow-up colonoscopy after colonic polypectomy    Sigmoid
Submucosal lesion 
I/Alive, NP (12) 
Colonoscopy for iron deficiency anemia  Previous low grade adenocarcinoma in sigmoid colon  Right colon
Ulcerated infiltrative lesion 
IIA/Alive, NP (12) 

C: case.


Ethn: ethnicity.


EBV: Epstein–Barr virus.


MSI: microsatellite instability.


FU: follow-up.


NS not specified.


NP: no progression.


A-A: African American.

Because of the lack of detailed pathogenetic information on colorectal LELCs, we have summarized the main characteristics from the available literature of gastric LELCs.

Gastric LELCs represent around 1 to 4% of all gastric tumors and 80% of them are VEB positive.9 VEB-positive tumors can be subdivided into ordinary type and LELC; 15–25% are LELC.10 The exact mechanism of EBV infection is not known. Gastric epithelial cells do not express CD21 (EBV receptor), but they may express another receptor, or they may interact directly with EBV-infected cells, such as lymphocytes or oropharyngeal epithelial cells.9 In addition, it has been reported that EBV and MSI are mutually exclusive in gastric LELC. Thus, they can be subdivided in VEB positive and MSI associated, which may have two separate carcinogenic pathways.11

In EBV-positive gastric cancer, endosonography typically shows a hypoechoic mass in the third layer, with a larger maximum thickness-to-width ratio than EBV-negative gastric cancer. Using computed tomography (CT), Maeda et al.12 found that early LELCs showed a focally thickened and enhanced mucosa and advanced lesions presented an obvious thickening of the wall. Kim et al.13 concluded that the most frequent morphology of gastric LELC was eccentric wall thickening (67.7%), with heterogeneous enhancement (67.2%) or central ulcerations (64.7%). Endoscopically, LELCs usually occur as depressed lesions surrounded by a raised margin, covered with normal mucosa.14 Preoperative biopsy usually renders insufficient tissue with many artifacts, making a histopathological diagnosis difficult.1

Macroscopically, LELCs are ulcerative, expansive and well circumscribed masses. They can be multiple and tumor size ranges from 4 to 32mm (mean: 10.1mm).9,13 When LELC invades the submucosa, a gastrointestinal stromal tumor (GIST), lymphoma, or carcinoid tumor should be suspected.

Microscopically they are undifferentiated carcinomas with cells arranged in nests, tubules or trabeculae with unclear margins (Regaud type), or isolated cells (Schminke type), with a dense intratumoral and peritumoral infiltration of lymphocytes. Plasma cells, eosinophils and neutrophils can be observed and the inflammatory infiltrate typically permeates tumor cells. In EBV-positive cases, EBV should be expressed in all tumor cells and sometimes can also be observed in some infiltrating lymphocytes.9 Differential diagnosis should be made with medullary carcinomas, poorly differentiated carcinomas and conventional adenocarcinomas with lymphoid stroma. Medullary carcinomas are arranged in syncytial sheets with well demarcated peripheral margins; the inflammation is principally peritumoral (Fig. 1C and D). At low power, there is an inner pale, solid area (composed mainly of epithelial tissue) and a surrounding darker zone (corresponding to the lymphoid infiltrate). These tumors are associated with microsatellite instability (MSI). Major studies on medullary carcinomas of the gastrointestinal tract concluded that these tumors have an organoid, solid, sheet-like or trabecular pattern with peri and intratumoral lymphocytes and consist of round to polygonal cells with high nuclear/cytoplasmic ratios and rounded nuclei with small central nucleoli.5,6 LECs and LELCs are made up of small clusters and aggregates of tumor that are broken up by large numbers of intratumoral lymphocytes. They have poorly demarcated margins (infiltrative growth pattern) due to the lymphocytic permeation; this infiltration tends to be intratumoral rather than peritumoral. These tumors may be associated with EBV, and occasionally with epigenetic silencing of MLH-1. In the stomach, most studies suggest that MSI and EBV are mutually exclusive.11

The main molecular abnormality in EBV-positive gastric cancer is CpG-island methylation by DNMT1 in many cancer-related genes. Some authors have suggested that BCL-2 could be the main inhibitor of apoptosis in VEB-positive gastric cancer and other studies showed that cerbB2 may be related to a poor prognosis.10

Surgery is the main treatment for LELC, although the best operative procedure is not clear. In most cases subtotal or total gastrectomy with lymphadenectomy is performed, but endoscopic submucosal dissection may suffice for submucosal lesions in high-risk patients. Gastric LELCs are sensitive to radiotherapy and chemotherapy, and adjuvant radiotherapy is usually used.1 LELC have been reported to have a better prognosis than conventional gastric cancers, but the reasons for this are unknown and the role of the lymphocytic infiltration, EBV or MSI status has not been elucidated.9,11

Other GI locations of this tumor: we have found 24 cases reported in esophagus in the literature: 11 were reviewed by Sashiyama et al.,15 and subsequently 13 cases have been reported. There are no differences between LELC and common esophageal cancers in terms of age distribution or male:female ratio. The majority was located in the mid-thoracic portion (75%) and the mean size was approximately 3.3cm. Some of these cases were associated with EBV infection.

In conclusion, the occurrence of LELC in large bowel is exceptional. It is crucial to differentiate between intestinal LELC and its mimics (mainly medullary carcinoma) to make a correct diagnosis. Clinically some cases have been found to be associated with Lynch syndrome and show macroscopic and imaging features that suggest LELC. They are usually EVB-negative by PCR or immunohistochemistry. LELCs have been reported to have a favorable prognosis and distinct molecular characteristics. However, the number of intestinal cases is too small to draw any conclusion on the epidemiology of this tumor. It remains to be seen whether this is merely a histopathological pattern or justifies any change in therapeutic options.

Ethical disclosuresProtection of human and animal subjects

The authors declare that no experiments were performed on humans or animals for this study.

Confidentiality of data

The authors declare that no patient data appear in this article.

Right to privacy and informed consent

The authors declare that no patient data appear in this article.


None declared.

Conflict of interest

The authors declare no conflict of interest.

J. Xue,H. Yu,J. Yan,N. Ren,Y. Yang,X. Wang
Non-Epstein-Barr virus-associated double primary lymphoepithelioma-like carcinoma of the esophagus and stomach: a case report and literature review
Int J Clin Exp Med, 8 (2015), pp. 10051-10057
Y. Mori,K. Akagi,M. Yano,H. Sashiyama,O. Tsutsumi,Y. Hamahata
Lymphoepithelioma-like carcinoma of the colon
Case Rep Gastroenterol, 7 (2013), pp. 127-133 http://dx.doi.org/10.1159/000348765
M. Vilor,Y. Tsutsumi
Localization of Epstein-Barr virus genome in lymphoid cells in poorly differentiated adenocarcinoma with lymphoid stroma of the colon
Pathol Int, 45 (1995), pp. 695-697
S. Samaha,O. Tawfik,R. Horvat,P. Bhatia
Lymphoepithelioma-like carcinoma of the colon: report of a case with histologic, immunohistochemical, and molecular studies for Epstein-Barr virus
Dis Colon Rectum, 41 (1998), pp. 925-928
G. De Petris,R. Lev,D.M. Quirk,P.R. Ferbend,J.R. Butmarc,K. Elenitoba-Johnson
Lymphoepithelioma-like carcinoma of the colon in a patient with hereditary nonpolyposis colorectal cancer
S. Kon,K. Kasai,N. Tsuzuki,M. Nishibe,T. Kitagawa,T. Nishibe
Lymphoepithelioma-like carcinoma of rectum: possible relation with EBV
Pathol Res Pract, 197 (2001), pp. 577-582 http://dx.doi.org/10.1078/0344-0338-00130
Y. Kojima,M. Mogaki,R. Takagawa,I. Ota,M. Sugita,S. Natori
A case of lymphoepithelioma-like carcinoma of the colon with ulcerative colitis
J Gastroenterol, 42 (2007), pp. 181-185 http://dx.doi.org/10.1007/s00535-006-1981-0
D. Delaney,R. Chetty
Lymphoepithelioma-like carcinoma of the colon
Int J Clin Exp Pathol, 5 (2012), pp. 105-109 http://dx.doi.org/10.1159/000348765
Z. Bittar,F. Fend,L. Quintanilla-Martinez
Lymphoepithelioma-like carcinoma of the stomach: a case report and review of the literature
Diagn Pathol, 8 (2013), pp. 184 http://dx.doi.org/10.1186/1746-1596-8-184
Y. Bai,Q. Gao,G. Ren,B. Wang,H. Xiang
Epstein-Barr virus-associated lymphoepithelioma-like gastric carcinoma located on gastric high body: two case reports
Indian J Pathol Microbiol, 57 (2014), pp. 463-466 http://dx.doi.org/10.4103/0377-4929.138775
K.L. Grogg,C.M. Lohse,V.S. Pankratz,K.C. Halling,T.C. Smyrk
Lymphocyte-rich gastric cancer: associations with Epstein-Barr virus, microsatellite instability, histology, and survival
E. Maeda,M. Akahane,H. Uozaki,N. Kato,N. Kayashi,M. Fukayama
CT appearance of Epstein-Barr virus-associated gastric carcinoma
Abdom Imaging, 34 (2009), pp. 618-625 http://dx.doi.org/10.1007/s00261-008-9444-0
C. Kim,H.J. Kim,D.H. Son,Y.S. Park,S.H. Park,J.S. Lee
Computed tomography findings for a gastric lymphoepithelioma-like carcinoma: how often does it present as a submucosal mass?
Eur Radiol, 26 (2015), pp. 3077-3085 http://dx.doi.org/10.1007/s00330-015-4122-4
J. Nishikawa,H. Yanai,Y. Mizugaki,K. Takada,M. TAda,K. Okita
Case report: hypoechoic submucosal nodules: a sign of Epstein-Barr virus-associated early gastric cancer
J Gastroenterol Hepatol, 13 (1998), pp. 585-590
H. Sashiyama,A. Nozawa,M. Kimura,E. Nomura,J.I. Tamaru,E. Ninomiya
Case report: a case of lymphoepithelioma-like carcinoma of the oesophagus and review of the literature
J Gastroenterol Hepatol, 14 (1999), pp. 534-539
Corresponding author. (Cristina Díaz del Arco crisdelarco@gmail.com)
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