Case 3 -

Lymphoepithelioma-like Carcinoma of Lung Claudia Y. Castro MD Department of Pathology, University of Texas Medical Branch Galveston, TX, USA

Clinical History: 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 Click to view with ImageScope Click to view with a Web-Based Viewer Gross finding: 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 margin. Histopathologic findings: 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. Diagnosis: Lymphoepithelioma-like carcinoma of the lung. Discussion: 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 [1]. 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 [2] of France and Smincke [3] 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 [4]. The reported incidence of LELC in the lung is 0.15 to 3.6% [5] in China and Japan. Since LELC of the lung was first reported by Begin et al. [5] in 1987, a total of 134 [4, 5, 6, 7, 8, 9, 10, 11] 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 [5, 6] 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 [4]. Exophytic endobronchial component in proximal lobar or segmental bronchi is rare and was described only in seven cases [4, 11]. Interestingly one case was described arising in an intra-lobar pulmonary sequestration [7]. Histologically 81% of LELC were Regaud type and 9% were Schmincke type [6]. 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 [4]. In one case the inflammatory infiltrate was so extensive, that simulate a inflammatory pseudo tumor [11]. The majority of lymphoid cells present in LELC show expression of both CD8 and TIA-1 by immunohistochemistry (T cell with cytotoxic potential) [4, 11]. 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. [4, 5, 6, 11.] Other microscopic features include prominent nuclear pleomorphism consisting in giant or multinucleated cells in more than 25% of the cells (18 cases) [6] , a in-situ component or pagetoid spread of the malignant cells in the bronchial epithelium (five cases) [4], focal amyloid deposition ( three cases) [4, 11], scattered foreign body and granulomatous reactions (9 cases) and the coexistence of LELC and tuberculosis in 2 cases [4, 11] . 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) [6] 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 Taiwanese) [4, 5, 6, 7, 9, 12] and all negative cases occurred in non-Asian patients (14 Caucasians, 2 Hispanics) [4, 8]. 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% . [4, 13.] Recent studies [11] 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 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 A: alive and well; AD: alive with disease; DOD: died of disease; DO-Other: died of other causes. 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