Case 2 -

Diagnosis - Lymphoepithelioma-like Carcinoma of the Lung Claudia Y. Castro University of Alabama Birmingham, Alabama

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Clinical History: The patient is a 49 year old Hispanic male who 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. 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 Case 2 - Figure 1 - LELC with "Schmicke's pattern" showing neoplastic cells growing diffusely and closely intermingled with inflammatory cells (low power). Case 2 - Figure 2 - LELC with cells, with ill defined cell border, vesicular nuclei, prominent nucleoli, intermixed with lymphocytes and plasma cells (medium and high power). Case 2 - Figure 3 - LELC with cells, with ill defined cell border, vesicular nuclei, prominent nucleoli, intermixed with lymphocytes and plasma cells (medium and high power). Case 2 - Figure 4 - LELC with cells, with ill defined cell border, vesicular nuclei, prominent nucleoli, intermixed with lymphocytes and plasma cells (medium and high power). Case 2 - Figure 5 - LELC showing strong keratin immunoreactivity in neoplastic cells. Case 2 - Figure 6 - LELC showing negative LCA in the neoplastic cells, whereas background lymphoid cells are positive. 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 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 Smincke3 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). Beside the lung, LELC has also been described in different anatomicalsites, 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% 9, 14, 23 in China and Japan. Since LELC of the lung was first reported by Begin et al.5 in 1987, a total of 1344-29 cases of primary LELC of the lung have been described in the English literature (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%), Twainese (26%) and Japanese (2%). The remaining patients were Caucasians (10%) or Hispanics (1.4%). The main complain at presentation was cough with blood stained sputum (50% of cases). Other symptoms included chest pain, body weight loss, and dyspnea. 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 23, 24. The relationship of LELC and smoking history is not statistical significant, in the reported series, fifty-one patients were non-smokers (38%), fifty patients were smokers (37%) and the smoking history was not known in 33 patients (24%). 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 8. Exophitic endobronchial component in proximal lobar to segmental bronchi is rare and was described only in seven 7,29. Fifty-six of the tumors were localized in the right lung, showing a right-side predominance. Interestingly one case was described arising in an intra-lobar pulmonary sequestration 25. Histologically 81% of LELC were Regaud type and 9% were Schmincke type 24. 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 8. In one case the inflammatory infiltrate was so extensive, that simulate a inflammatory pseudo tumor 29. The majority of lymphoid cells present in LELC show expression of both CD8 and TIA-1 by immunohistochemistry (T cell with cyto-toxic potential) 21, 29. The infiltrate of lymphocytes is also seen the metastastic 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, 12, 16, 21, 23, 24, 29. Other microscopic features include prominent nuclear plemorphism consisting in giant or multinucleated cells in more than 25% of the cells (18 cases) 24 , a in-situ component or pagetoid spread of the malignant cells in the bronchial epithelium (five cases)12, focal amyloid deposition ( three cases) 12, 29 , scattered foreign body and granulomatous reactions (9 cases) and the coexistence of LELC and tuberculosis in 2 cases 18, 24. Vascular or lymphatic were rarely identified. Electron microscopy in one case demonstrated desmosomes between malignant cells and poorly formed tonofilament within the cells 4. 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. Distant metastasis of nasopharyngeal carcinoma is also highly related to the original extent of the primary tumor and the bulk of cervical lymph node involvement. 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 spindle, 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 a primary neoplasia of the lung. Thymomas may be composed by round-to-oval cytokeratin positive epithelial cells admixed with variable number of T lymphocytes. However the epithelial cells of thymoma show a much 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 the series of LELC, surgery was the only treatment in 69 patients (52%), followed by surgery and radiation therapy in 21 patients (16%), chemotherapy alone in eleven (8%), radiation therapy in eight (6%), surgery and chemotherapy in 6 (4%), surgery, radiation and chemotherapy in 3 (2%) and radiation only in 2 (1%). Four patients (stage IIIb and IV ) declined treatment.67 The type of treatment was not reported in 10 patients (7%). In relation to prognosis of LELC only one series (Hang 24) 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 and for patients with non-LELC is seen in table 2. Table 2. Survival of LELC compared to Non-LELC of the Lung Tumor Type: LELC Non-LELC Time: 2-years 5-years 2-years 5-years Overall Survival: 80% 53% 59% 39% Stage I: 75% 37% 74% 59% Stage II: 100% 62% 55% 30% Stage III and IV: 81% 61% 50% 21% Han AJ, et al. Am J Clin Pathol. 2001;115:841-50. This series found significant difference in overall survival for patients with LELC compared with patients with non-LELC (P<0.5) particularly in patients with stage II –IV. No difference in survival was observed in between patients in stage I disease. 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. Sex, clinical stage did not correlate with expression of EBER, LMP-1 or VCA . 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) 6, 7, 9, 10, 12, 14, 16, 17, 19-25, 27, 29, 30, and all negative cases occurred in non-Asian patients (14 Caucasians, 2 Hispanics)4, 6, 8, 13-15, 26. All the EBV-positive tumors were examined by RNA ISH, and all of the studies localized the EBV genome to the neoplastic cells. In addition, 11 tumors shown to be positive for EBV by ISH were shown by southern blot to have monoclonal EBV genomic pattern.9, 16. 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. Some investigators have observed a strong association between Epstein-Barr virus (EBV) and LELC in the salivary gland, stomach, hepatobiliary tract, middle ear, larynx, thymus, cervix, ureter, and skin3. There are LELC at a specific anatomical sites that have never been proved to be associated with an EBV. This includes LELCs of the floor of the mouth, tonsil, vagina, bladder, renal pelvis, and thyroid gland 4. There is no good explanation for EBV being commonly present in certain anatomic sites and not in others. In the past it was believed that EBV was associated only with LELC arising from foregut derivates (salivary gland, stomach, thymus, and lung). However, EBV is associated with LELC in a wide range of locations that do not fit in with any anatomic or embryologic derivation. Therefore the EBV associated with LELC is related to racial or geographic influences rather than to the anatomic location of the tumor. Specifically, EBV is associated with LELC of the salivary gland and lung, only in Asian patients. On the other hand, the association of EBV with LELC at other sites, e.g., gastric, thymic, skin, is independent of race. The pattern observed in patients with LELC of the lung may be analogous to that seen in Burkitt's lymphoma which shows a virtual 100% association with EBV in patients of African descent, but only 20% associated in patients of non-African descent. The absence of EBV genome in most LELC cases implies, however, that EBV is not a requisite factor in the etiology or pathogenesis of LELC. 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% .16, 21, 31 Eight cases of squamous cell carcinoma10,20 and two cases of adenocarcinoma10 have also been positive for EBV, as shown by ISH. Recent studies 29 show that most cases (95%) of LELC are positive for BCL2 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. References WHO. The World Health Organization histological typing of lung tumors. Travis WD, Colby TV, Corrin B, et al: Histological Typing of Lung and Pleural Tumours. 3rd ed. New York:Springer 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. Begin LR, Eskandari J, Joncas J, Panasci L: Epstein-Barr virus related lymphoepithelioma-like carcinoma of lung. J Surg Oncol 36:280-283, 1987 Butler AE, Colby TV, Weiss L, Lombard C: Lymphoepithelioma-like carcinoma of the lung. Am J Surg Pathol 13:632-639, 1989 Gal AA, Unger ER, Koss MN, Yen TS: Detection of Epstein-Barr virus in lymphoepithelioma-like carcinoma of the lung. Mod Pathol 4:264-268, 1991 Miller B, Montgomery C, Watne AL, et al: Lymphoepithelioma-like carcinoma of the lung. J Surg Oncol 48:62-68, 1991 Pittaluga S, Wong MP, Chung LP, Loke SL: Clonal Epstein-Barr virus in lymphoepithelioma-like carcinoma of the lung. 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Diagn Mol Pathol 1:246-255, 1992 Zhang L, Liu H, Wang Z: Detection of EBV in pulmonary carcinoma by in situ hybridization. Chin J Pathol 25:1-3, 1996. 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 5 1987 1 F Phillipin non 1 Stage I 1 sur + rad DOD 6 yr. Butler 6 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 7 1991 1 M Chinese non 1 Stage III 1 sur + rad 1 A & W 12m Miller 8 1991 1 F Caucasian smoker 1Stage II 1 surg 1 AWD 13m Pittaluga 9 1993 & Chang 12 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 10 1994 1 F Japanese unknown 1 Stage III 1 surg unknown Chow 11 1995 2 2M Chinese unknown 2 Stage I 2 surg 2 A&W 6-12m Chang 12 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 13 1995 2 M F White 2 smoker 2 unknown 2 surg 1 DOD 48 m. 1 A & W 18 m. Higashiyama 14 1995 2 2M Japanese unknown 2 Stage I 2 unknown 2 A & W 54-55m Wockel 15 1995 2 F M White 2 unknown Stage I unknown 2 unknown 2 unknown Wong 16 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 17 1997 1 F Chinese non 1 Stage III 1 che+surg A & W 20m Frank 18 1997 1 M Caucasian non 1 Stage II 1 surg+che A&W 8m Chang 19 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 20 1998 5 2M 3F Taiwain non in 5/5 (3) I-II (2) III-IV 5 unknown 2 A & W 24 m. Kasai 21 1999 1 M Chinese unknown 1 Stage III 1 chem A & WD 24 m. Murashi 22 1999 1 F Chinese unknown unknown 1 unknown unknown Author Case # Sex Race Smoking Stage Treatment Follow-up Hang 23-24 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 Hekelaar25 2000 1 F Chinese non 1 Stage I 1 surg 1 A&W 4 y Barroso26 2000 1   White smoker 1 Stage III 1 chem DOD 2m. Ho27 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 Ngan28 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-29 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 * Chang reported 11 cases, but 2 were previously reported by Pitaluga.