Moderators: Dr. Elizabeth Brambilla, Dr. John English and Dr. Donald Guinee
Case 3 -
Lymphoepithelioma-like Carcinoma of Lung
Claudia Y. Castro MD
Department of Pathology, University of Texas Medical Branch
Galveston, TX, USA
49 year old Hispanic male complained of cough for 2 months. His past medical history was significant
only for heavy smoking (2 pack of cigarettes /day/ 15 years). A chest radiograph showed a
well-circumscribed nodule in the periphery of the right upper lobe. Patient underwent wedge resection.
After frozen section diagnosis, a completion of the lobectomy was performed.
Case 3 - Slide 1
The specimen consisted if a wedge biopsy of lung (4.8 x 2.3
x 2.2 cms) containing a relative well circumscribed, 1.4 cms subpleural nodule. The cut surface was
white, firm and focally necrotic. The nodule was located at 1.0 cms from the staple surgical resection
Tumors consisted of solid nests of
undifferentiated tumor cells in a syncytial arrangement surrounded by heavy lymphoplasmacytic infiltrate.
Tumor cells stained positively for keratin, but negative for LCA and EBV.
Lymphoepithelioma-like carcinoma of the lung.
Lymphoepithelioma-like carcinoma (LELC) is a rare form of lung
cancer that has been recently recognized as a subtype of large cell carcinoma of the lung and has been
included in the 1999 and 2004 Histological Classification of Lung Tumors formulated by the World Health
Organization . This type of tumor as its name indicates has histologic features similar to
those of undifferentiated carcinoma of the nasopharynx (lymphoepithelioma). The term "lymphoepithelioma"
was introduced independently by Regaud 
of France and Smincke  of Germany in 1921,
to describe an undifferentiated carcinoma of the nasopharynx with an intense lymphocytic component.
There are two histologic patterns. The first one (Regaud type) displays well-defined epithelial nests of
cells in a syncytial growth pattern surrounded by a heavy lymphoplasmacytic infiltrate. The second
pattern is characterized by tumor cells growing in a diffuse manner intermixed, with lymphocytes and
plasma cells, mimicking malignant lymphoma (Schmincke type).
Besides the lung, LELC has also been described in different anatomical sites, including
the salivary gland, esophagus, stomach, colon, hepatobiliary system, middle ear, larynx, thymus, uterus,
vagina, ureter, bladder, renal pelvis, thyroid gland, skin and breast . The
reported incidence of LELC in the lung is 0.15 to 3.6%  in China and Japan.
Since LELC of the lung was first reported by Begin et al.  in 1987, a total of 134
cases of primary LELC of the lung have been described in the English literature (see table 1). In
this series, there was a slight male predominance (51%) and the patient's age ranged from 8 to 80 years,
with a mean of 54 years. Similar to undifferentiated nasopharyngeal carcinoma, most of the LELC of the
lung have been described in Asian patients (88%), including Chinese (73%), Taiwanese (26%) and Japanese
(2%). The remaining patients were Caucasians (10%) or Hispanics (1.4%). The main complaint at
presentation was cough with blood stained sputum (50% of cases). The length of the symptoms varied from
1 to 12 months (mean duration 2.6 months). In thirty-one percent of the cases the patients
were asymptomatic and the lesion was found in a routine radiograph of the chest
On gross examination the tumors ranged from 1.2 to 11 cm in the greatest dimension. Most tumors were
solitary, white, firm, well circumscribed and peripheral. The majority of the tumors (53%) had foci of
necrosis often central in location and only in one case the necrosis was so extensive that produced a
cavitary mass which was seen on X-ray . Exophytic endobronchial component in proximal lobar
or segmental bronchi is rare and was described only in seven cases
case was described arising in an intra-lobar pulmonary sequestration .
Histologically 81% of LELC were Regaud type and 9% were Schmincke type . The tumor cells
were characterized by ill-defined borders with scanty eosinophilic cytoplasm; round, ovoid, or
spindle-shaped nuclei; vesicular chromatin; and one or two distinct eosinophilic nucleoli. High mitotic
rates ranging from 3 to 30 mitoses per 10 high power fields were usually found (mean 10 m/hpf). The
inflammatory infiltrate in all the cases were moderate to severe and was usually composed by lymphocytes
and plasma cells, with occasional lymphoid follicles. Only in few cases eosinophils have been described
. In one case the inflammatory infiltrate was so extensive, that simulate a inflammatory
pseudo tumor . The majority of lymphoid cells present in LELC show expression of both CD8
and TIA-1 by immunohistochemistry (T cell with cytotoxic potential)
The infiltrate of
lymphocytes is also seen the metastatic sites (such as bone, etc).
A focal spindle component (23 cases), glandular (2 cases) or squamous differentiation (10 cases) have
also been described in LELC.
Other microscopic features include prominent nuclear
pleomorphism consisting in giant or multinucleated cells in more than 25% of the cells (18 cases) 
, a in-situ component or pagetoid spread of the malignant cells in the bronchial epithelium (five
cases) , focal amyloid deposition ( three cases)
scattered foreign body and
granulomatous reactions (9 cases) and the coexistence of LELC and tuberculosis in 2 cases
. Vascular or lymphatic invasion was rarely identified.
The differential diagnosis of LELC of the lung includes metastasis from a nasopharyngeal carcinoma,
malignant lymphoma and malignant melanoma. Histologically, the primary LELC of the lung cannot be
distinguished from a metastatic nasopharyngeal carcinoma, however, clinical history, endoscopic
examination and random biopsies of nasopharynx, combined with computed tomography could exclude primary
NPC. Distant metastases from nasopharyngeal carcinoma are observed in 20% of patients and usually occur
in the bones, followed by the liver and lungs. LELC, particularly of the Schimmicke type can simulate
lymphoma. In such instances a panel of immunohistochemical stains using keratin and LCA will help
resolve the problem. In LELC cytokeratin-positive cells are characteristically patchy in distribution.
Malignant melanoma is the great simulator. It can have spindled plasmacytoid cells with prominent
nucleoli. A panel of immunohistochemical stains including S-100 and HMB45 is helpful in this setting.
All the major subtypes of carcinoma of the lung may occasionally be associated with a prominent
lymphoid reaction and when it happens they need to be differentiated from LELC. Most lung carcinomas
with prominent lymphoid stroma show sharp demarcation between the tumor cells nests and the lymphoid
reaction. This contrast with LELC in which there is intermingling of the tumor cells with the lymphoid
cells. In addition the tumor cells of LELC show distinctive cytologic features including a syncytial
cytoplasm, vesicular nuclei and prominent nucleoli. Other differential diagnosis will include thymoma,
which may present as a primary tumor of the lung. Thymomas are composed by uniform round-to-oval
cytokeratin positive epithelial cells admixed with variable number of T lymphocytes. The epithelial
cells of thymoma have a smaller nucleolus than the cells of LELC and the tumor is separated by fibrous
bands (organoid pattern).
In most patients, LELC was discovered at a late stage. Specifically, at the time of presentation,
there were 46 patients (34%) with a Stage I disease, 23 patients (17%) with a Stage II disease, 41
patients (30 %) with a Stage III disease, and 17 patients (13%) with a Stage IV disease. The stage of
the tumor was not documented in seven cases (5%).
In relation to prognosis of LELC only one series (Hang)  compared the survival of 32 cases
of LELC and 84 cases of non-LELC (33 squamous cell carcinomas, 36 adenocarcinomas, 6 adenosquamous and 9
large cell carcinomas). In this series the 2- and 5- year overall survival rate for patients with LELC
was better (80% and 53%, respectively) than the one for patients with non-LELC (59% and 39%).
Attempts to find prognostic factors in LELC have shown that tumor recurrence and amount of necrosis
(25% of more of the tumor) are associated with poor prognosis. Other indicators including age, sex,
smoking, and lymph node metastasis at time of diagnosis, pathologic type (Regaud or Schmincke),
angio-invasion, nuclear pleomorphism, intensity and labeling index of EBER-1 and LMP1 expression are not
related to survival.
The relationship of EBV and LELC in general is controversial. Of the 134 reported cases of primary
LELC of the lung, 124 (92%) cases were tested for EBV, and of those, 109 (88%) were positive for the
virus. Of particular note, all EBV-positive cases occurred in Asian patients (79 Chinese, 2 Japanese, 28
and all negative cases occurred in non-Asian patients (14 Caucasians, 2
All the EBV-positive tumors were examined by RNA ISH, and all of the studies
localized the EBV genome to the neoplastic cells. These collective findings indicate that the
association of EBV with the lung LELC appears to depend on racial and geographic factors and has only
been observed for specific ethnic and geographic groups including Chinese, Japanese, Taiwanese, and
Eskimos, but not in patients from Western countries.
Recently it was found that EBV-associated cancers are not restricted to typical LELC of the lung. EBV
has also been observed in cases of non-small cell carcinoma of the lung (NSCLC). The reported incidence
of EBV in conventional NSCLC in the latest Chinese and Japanese series ranged from 6.2% to 37%
Recent studies  show that most cases (95%) of LELC are positive for BC-2 and rarely (17%)
are positive for P53. Compared to reported BCL-2 expression of 20% of (NSCLC).
In summary, LELC of the lung is a rare, distinct clinicopathologic entity. LELC usually presents as a
solitary nodule and most patients have late-stage disease at presentation. Microscopic features of LELC
in the lung may include focal, squamous or glandular differentiation. The differential diagnosis
includes melanoma, lymphoma and metastatic NPC. The association of EBV and LELC in the lung appears to
depend on racial and geographic factors. The absence of the EBV genome in the LELC suggests, however,
that EBV is not an important factor in the pathogenesis of LELC of the lung.
Table 1: Demographic characteristics, tumor stage, treatment and follow-up of LELC of the lung reported in the Literature
A: alive and well; AD: alive with disease; DOD: died of disease; DO-Other: died of other causes.
|Author ||Case # ||Sex ||Race ||Smoking ||Stage ||Treatment ||Follow-up|
|Begin 60 ** 1987 ||1 ||F ||Phillipino ||non ||1 Stage I ||1 sur + rad ||DOD 6 yr.|
|Butler 61** 1989 ||4 ||1M 3F ||3 Whites Chinese ||3 smoker 1 non ||3 Stage I 1 Stage III ||3 surg 1 sur+rad ||3 A & W 1.5-9y 1 A & WD 1.5yr|
|Gal 62 ** 1991 ||1 ||M ||Chinese ||non ||1 Stage III ||1 sur + rad ||1 A & W 12m|
|Miller 63** 1991 ||1 ||F ||Caucasian ||smoker ||1Stage II ||1 surg ||1 AWD 13m|
|Pittaluga 64 1993 & Chang 67** ||5 ||5M ||Chinese ||unknown ||1Stage I 1 Stage II 3 unknown ||5 surg ||3 A & W 0.5-2 y 2 lost F-u|
|Kasai 65** 1994 ||1 ||F ||Japanese ||unknown ||1 Stage III ||1 surg ||unknown|
|Chow 66** 1995 ||2 ||2M ||Chinese ||unknown ||2 Stage I ||2 surg ||2 A&W 6-12m|
|Chang 67** 1995 ||9* ||4M 5F ||Chinese ||2 smokers 6 non 1 unknown ||6 Stage I 2 Stage III 1 stage IV ||7 surg 1 decline 1 bx ||4 A & W 5-24m 1 A & WD 18m 1 DOD 4m 3 recent cases|
|Ferrara 68** 1995 ||2 ||M F ||White ||2 smoker ||2 unknown ||2 surg ||1 DOD 48 m. 1 A & W 18 m.|
|Higashiyama 69 1995 ||2 ||2M ||Japanese ||unknown ||2 Stage I ||2 unknown ||2 A & W 54-55m|
|Wockel 70** 1995 ||2 ||F M ||White ||2 unknown ||Stage I unknown ||2 unknown ||2 unknonw|
|Wong 71** 1995 ||9 ||8M 1F ||Chinese ||4 smokers 4 non I unknown ||4 Stage I 2 Stage II 3 Stage III ||9 surg ||7 A & W 30-52 m A & WD 27-36 m|
|Curcio 72** 1997 ||1 ||F ||Chinese ||non ||1 Stage III ||1 che+surg ||A & W 20m|
|Frank 73** 1997 ||1 ||M ||Caucasian ||non ||1 Stage II ||1 surg+che ||A&W 8m|
|Chang 74** 1998 ||9 ||5M 4F ||Chinese ||1 smoker 8 non ||1 Stage I 1 Stage II 2 stage III 5 stage IV ||5 che+rad 2 surg+ che 1 surg+rad 1 che ||2 A & W 18-20m 4 A & WD 6-18m 3 DOD 5-26m|
|Chen 75** 1998 ||5 ||2M 3F ||Taiwain ||non in 5/5 ||(3) I-II (2) III-IV ||5 unknown ||2 A & W 24 m.|
|Kasai 76** 1999 ||1 ||M ||Chinese ||unknown ||1 Stage III ||1 chem ||A & WD 24 m.|
|Murashi 77** 1999 ||1 ||F ||Chinese ||unknown ||unknown ||1 unknown ||unknown|
|Hang 5 2000-2002 ||32 ||22M 10F ||Chinese ||14 heavy 12non ||12 Stage I 8 Stage II 11 Stage III 1Stage IV ||14 surg 14 surg+rad 1 surg+che 3 su+ch+r ||12 A&W 24-172m 3 A&WD 12-120m 11 DOD 14-72m 6 Unkn|
|Hekelaar7 2000 ||1 ||F ||Chinese ||non ||1 Stage I ||1 surg ||1 A&W 4 y|
|Barroso8 2000 ||1 || ||White ||smoker ||1 Stage III ||1 chem ||DOD 2m.|
|Ho9 2000 ||3 ||1M 2F ||Chinese ||smoker 2 non ||1 Stage III 2 Stage IV ||2 che 1 che+ rad ||3 AWD 4-13 m|
|Castro4 2001 ||6 ||4M 2F ||4 White 2 hispanic ||6 smokers ||4 Stage I 1 Stage II 1 Stage III ||5 surg 1 surg+rad ||6 A&W 18-28m|
|Ngan10 2002 ||11 ||11F ||Chinese || ||2 Stage II 6 Stage III 3 stage IV ||2 surgery 3 chem 2 rad 2 sur+rad 2 no Tx ||3 A&W 19-33m 2 A&WD 3-9m 4 DOD 6-74m|
|Chang Y-11 2002 ||23 || ||Twainese ||6 smokers 17 non ||7 Stage I 4 Stage II 8 stage III 1 stage IV ||17 surgery 3 chem 1 Ch+surg 2 Ch+rad ||12 ALIVE 4-74m 2 DOD 17-18m 1 DO-Other 2.5m 2 lost Fu 7-14m|
- Chang reported 11 cases, but 2 were previously reported by Pitaluga.
- ** see references 60-77 from reference 4 (Castro et-al, 2001). Bibliography of references 60-77 are not provided in this article due to limitations of space (as per instructions hand out not more than 4 pages in length, including references).
- WHO. The World Health Organization histological typing of lung tumors. Travis WD, Brambrilla E, et al: Histological Typing of Lung and Pleural Tumours. 4th ed. 2004. IRC Press, Lyon (France).
- Regaud C, Reverchon L. Sur un casd'epithelioma epidermoide developpe' dans le massif maxillaire superieur. Rev Laryngol Otol Rhinol. 1921; 42:369-378.
- Schmincke A. Uber lymphoepitheliale Geschwulste. Beitr pathol. Anat Allg Pathol. 1921;68: 161-170.
- Castro CY, Ostrowski ML, Barrios R, Green LK, Popper HH, Powell S, Cagle PT,Ro JY. Relationship between Epstein-Barr virus and lymphoepithelioma-like carcinoma of the lung: a clinicopathologic study of 6 cases and review of the literature. Hum Pathol. 2001 Aug;32(8):863-72.
- Han AJ, Xiong M, Zong YS. Association of Epstein-Barr virus with lymphoepithelioma-like carcinoma of the lung in southern China. Am J Clin Pathol. 2000;114:220-6.
- Han AJ, Xiong M, Gu YY, Lin SX, Xiong M. Lymphoepithelioma-like carcinoma of the lung with a better prognosis. A clinicopathologic study of 32 cases. Am J Clin Pathol. 2001;115:841-50.
- Hekelaar N, van Uffelen R, van Vliet AC, Varin OC, Westenend PJ. Primary lymphoepithelioma-like carcinoma within an intralobular pulmonary sequestration. Eur Respir J. 2000;16:1025-7.
- Barroso A, Nogueira R, Lencastre H, Seada J, Parente B. Primary lymphoepithelioma-like carcinoma of the lung. Lung Cancer. 2000;28:69-74.
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- Chang YL, Wu CT, Shih JY, Lee YC. New aspects in clinicopathologic and oncogene studies of 23 pulmonary lymphoepithelioma-like carcinomas. Am J Surg Pathol. 2002;26:715-23.
- Chang L, Chen YY, Shibata D, Weiss L: Description of an in situ hybridization methodology for detection of Epstein-Barr virus RNA in paraffin-embedded tissues, with a survey of normal and neoplastic tissue. Diagn Mol Pathol 1:246-255, 1992
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