eISSN: 2084-9869
ISSN: 1233-9687
Polish Journal of Pathology
Current issue Archive Manuscripts accepted About the journal Supplements Abstracting and indexing Subscription Contact Instructions for authors
SCImago Journal & Country Rank
1/2018
vol. 69
 
Share:
Share:
more
 
 
Case report

Lymphoepithelioma-like breast carcinoma

Nektarios Koufopoulos, John Syrios, Asimina Papanikolaou, Ioannis Misitzis, Kasiani A. Kapatou, Dionysis Dimas, Lubna Khaldi

Pol J Pathol 2018; 69 (1): 98-104
Online publish date: 2018/05/07
Article file
Get citation
ENW
EndNote
BIB
JabRef, Mendeley
RIS
Papers, Reference Manager, RefWorks, Zotero
AMA
APA
Chicago
Harvard
MLA
Vancouver
 
 

Introduction

Nasopharyngeal lymphoepithelioma is a well-defined entity first described in 1921 by Regaud, Reverchon, and Schminke [1, 2]. Two distinct histological patterns have been described: Schminke pattern, consisting of isolated tumour cells, and Regaud pattern, in which tumour cells are arranged in nests, cords, or syncytial appearance. In both patterns neoplastic cells are associated with a densely infiltrated lymphoid stroma. The type of architectural pattern is not related to prognosis. Lymphoepithelioma-like carcinoma (LELC) is a poorly differentiated carcinoma occurring outside the nasopharynx, which displays identical histological features to its nasopharyngeal counterpart. It has been reported in several anatomic sites including breast [3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25], colon [26], esophagus [27], kidney [28], lacrimal gland [29, 30], larynx [31], hepatobiliary system [32, 33], lungs [34], major and minor salivary glands [35, 36, 37, 38], orbital adnexa [39], prostate [28], skin [40], stomach [41], thymus [42], thyroid [43], trachea [44], ureter [45], urinary bladder [46], uterine cervix [47], vagina [48], and vulva [49, 50]. Epstein-Barr virus (EBV) has been associated with LELC in several anatomic sites, such as nasopharynx, salivary gland, stomach, and thymus, but not in non-foregut derived tissues such as skin, uterine cervix, oral cavity, and urinary bladder [51].
Lymphoepithelioma-like carcinoma of the breast (LELC-B) was first described in 1994 by Kumar and Kumar [3]. In total, 33 cases have been reported in the English literature. The diagnosis may be challenging, especially on frozen sections, due to its morphological similarity to medullary carcinoma, lymphocyte-rich invasive carcinoma of ductal or lobular type, non-Hodgkin’s, and Hodgkin’s lymphoma. Herein, we review 33 previously reported cases of LELC-B additionally to a case recently encountered in our pathology department that proved to be diagnostically challenging.
Due to the rarity of this entity no solid evidence regarding the optimal treatment strategy exists. Patients with LELC-B are excluded from randomised controlled trials, and their management is therefore based on anecdotal cases or published case reports [23].

Case report

A 57-year-old patient with no previous history was admitted due to palpable lymphadenopathy of the left axilla. On clinical examination a small palpable breast lump in the upper outer quadrant of the left breast was identified, followed closely by FNAC, which was positive for malignancy. Mammography revealed an asymmetrical mass close to the pectoralis major muscle measuring 15 mm surrounded by microcalcifications. Clinically enlarged lymph nodes were identified by an ultrasound in the ipsilateral axilla. Radiological examination for cancer staging was subsequently performed and showed a multilobulated solid mass in the upper outer quadrant of the breast together with enlarged axillary lymph nodes and a left adrenal gland adenoma. No distant disease was identified. Conn’s syndrome and hypertension were also diagnosed during her hospitalisation. The patient underwent a lumpectomy with axillary lymph node excision along with left laparoscopic adrenalectomy at the same surgical procedure.
Grossly, the tumour was relatively well circumscribed, measuring 22 mm, on a cut surface it had a relatively hard consistency. Microscopically, on low-power examination the tumour had a nodular appearance separated by fibrous septa. Higher-power examination revealed small tumour islands, cords, and single cells displaying a moderate degree of atypia and scanty cytoplasm. They were surrounded and intermingled predominantly by lymphocytes (Fig. 1); lymphoid follicles and occasional plasma cells, eosinophils, and histiocytes were also noticed. Occasionally the tumour sheets were permeated and destroyed by lymphocytes resulting in so-called lymphoepithelial lesions. In situ component, either ductal or lobular, was not identified. Mitotic figures were few.
Metastatic disease was found in 8 of 13 lymph nodes (Fig. 2).
The presentation of the patient with extensive lymphadenopathy and the predominant lymphoepithelial component of the tumour in combination with the absence of in situ structures rendered the suspicion of a lymphoproliferative disorder and hence an experienced hem-pathologist (A.P) consultation was carried out. Therefore, the immunohistochemical staining of the lymphocytic infiltrate demonstrated positivity for lymphoid markers CD20 and CD3, with predominance of T-lymphocytes (CD3+, CD4+ > CD8+). Studies for light chain expression by the B-lymphocytes (CD20+) and plasma cells show polytypic cell population SIg/CIg() ≥ SIg/CIg().
Additional immunohistochemical indices revealed positivity of tumour cells for the epithelial markers AE-1/AE-3, Cytokeratin 8/18, EMA, Cytokeratin 7 (Fig. 3), and E-Cadherin. Negativity was noticed for Cytokeratin 20, ER, PR, C-ERB-2, and CD-117. Ki-67 showed positive staining in 80% of the tumour nuclei. Epithelial markers were applied to lymph nodes as well. Tumour cells showed positive staining for AE-1/AE-3 and Cytokeratin 7 (Fig. 4).
In situ hybridisation to detect Epstein-Barr virus (EBV) yielded negative results. Type 16 HPV was detected by PCR and in situ hybridisation techniques.
The diagnosis of LELC-B was made. The patient showed no postoperative complications and was discharged seven days after surgery. She received adjuvant therapy with a combination of chemotherapy and RT; 36 months later there is no evidence of recurrence or metastasis.

Discussion

Lymphoepithelioma-like carcinoma (LELC) is an undifferentiated carcinoma analogous to the nasopharyngeal lymphoepithelial carcinoma. Concerning the breast, it is a rare entity with only 33 cases (32 patients) described in the literature, the majority being single case reports. The clinical characteristics of the previous reports are summarised in Table I. Morphologically, tumour necroses were identified in two patients in the Dadmanesh series as well as in five more cases [5, 10, 15, 19, 24]. A lobular variant of LELC-B has been reported by some authors [3, 4, 7, 9] associated with LCIS [3, 4, 7], pagetoid spread [4], or with atypical lobular hyperplasia [9]. Ductal carcinoma in situ was not identified in any of the previous cases. In three of the cases there was association with sclerosing lymphocytic lobulitis in the surrounding breast parenchyma [6, 19, 20]. Kurose et al. reported glandular differentiation on electron microscopy [10]. Dadmanesh et al. described in their series one case of familial tumour with established BRCA mutation [5]. Dinniwell et al. reported CD-117 positivity in their tumour [18]. There is no evidence of association with EBV either by ISH [4, 5, 8], immunohistochemistry [7], or PCR [4]. Our case was negative for EBV assessed with in situ hybridisation. The reviewed literature indicated two cases of LELC-B in association with HPV [12, 17]. The case in hand was examined for low- and high-risk HPV; detection of type 16 virus was evident using PCR and in situ hybridisation techniques.
Lymph node metastasis was found in seven of the cases that reported nodal status. Our case was treated with BCS together with axillary lymph node dissection, and metastatic disease was found in eight lymph nodes, thus being the only case with N2 disease.
In the present case, the infiltration of axillary lymph nodes by the tumour mandated the use of systemic adjuvant treatment. The patient was therefore offered adjuvant chemotherapy based on the AC – T regimen. This regimen consists of four cycles of doxorubicin and cyclophosphamide administered successively with four cycles of paclitaxel administered intravenously every 21 days. After the completion of adjuvant chemotherapy the patient was offered adjuvant radiotherapy. She is currently leading an active life and is free of disease 36 months after diagnosis. We attribute the optimal outcome partly to the incorporation of the taxanes to an anthracycline-based chemotherapy and mainly to the multidisciplinary approach of this rare disease.
LELC-B may be under-diagnosed due to its similarity to lymphocyte-predominant breast carcinoma (LPBC) of ductal or lobular type. In fact, their resemblance is so intense that some authors have debated whether LELC-B is a distinct entity [8].
The differential diagnosis includes medullary carcinoma (MC), atypical medullary carcinoma (AMC), and lymphoproliferative disorders such as non-Hodgkin’s lymphoma and Hodgkin’s lymphoma.
MC is defined as a special type of breast carcinoma with favourable prognosis. Its histological recognition is based on a number of histological criteria proposed by Ridolfi et al., including syncytial growth pattern in more than 75%, complete microscopic circumscription, moderate to marked lymphoid stromal infiltration, high nuclear grade and numerous mitoses, lack of in situ component, or gland formation [54].
AMC diagnosis requires that the tumour fulfils the first two criteria and has the possibility of missing up to two of the remaining criteria. LELC-B may show syncytial growth pattern, although not in >75%, usually has an infiltrative pattern lacking circumscription, and its cells are not as pleomorphic as in MC or AMC [5]. Another useful feature is that in MC and AMC the lymphoid infiltrate does not obscure or intermingle with the epithelial cells [8]. It should be noted that in the latest (fourth) edition WHO classification of tumours of the breast, both MC and AMC are collectively termed as carcinoma with medullary features [55].
Lymphocyte-rich invasive breast carcinoma or LPBC is defined as a carcinoma with at least 50-60% inflammatory stroma [56]. The distinction between LELC-B and LPBC lies in the amount of the lymphocytic infiltrate, which in LPBC should not be as intense as in LELC-B, thereby obscuring the neoplastic cells. Also, certain architectural and cytological characteristics may prove helpful in the differential diagnosis [5].
Morphologically it may be difficult to distinguish the Schminke pattern of LELC-B from non-Hodgkin’s and Hodgkin’s lymphoma. In the literature, in a number of cases NHL was the main diagnostic challenge on microscopic examination [6, 8], and some cases were initially diagnosed as NHL [5, 18, 25]. Moreover, the presence of binucleated and/or multinucleated cells, thus bearing strong resemblance to Hodgkin’s Lymphoma [6, 11], are cases that need further investigation. Nonetheless, the differential diagnosis of LELC-B on morphological bases is mainly from Hodgkin’s Lymphoma and NHL, therefore of exclusion diagnosis, a panel of immunohistochemical staining showing positivity for epithelial differentiation AE-1/AE-3, EMA, Cytokeratin 8/18, and Cytokeratin 7 in combination to lymph-marker CD3, CD20, CD15, CD30, and ALK-1 is needed to solve the ambiguity.

Conclusions

LELC-B is a rare disease, considered as the nasopharyngeal lymphoepithelioma counterpart, which pathologists should be aware of. Specific features that help distinguish this entity include nodular mass dominated by dense inflammatory cells that permeate and destroy tumour cells separated by fibrous septa. Tumour cells display a moderate to high degree atypia, small nucleoli, and scanty cytoplasm. Multinuclear features may be present. The in situ component, whenever present, is always of lobular type. Due to the lack of evidence regarding the optimal management of this disease, it is recommended that experience between clinicians be shared in literature and treatment be designed in a multidisciplinary approach.

The authors declare no conflicts of interest.

References

1. Schmincke A. On the subject of lymphoepithelial tumours [German]. Beitr Pathol Anat 1921; 68: 161-170.
2. Regaud C, Reverchon L. A case of squamous epithelioma in the body of the superior maxillary [French]. Rev Laryngol Otol Rhinol 1921; 42: 369-378.
3. Kumar S, Kumar D. Lymphoepithelioma-like carcinoma of the breast. Mod Pathol 1994; 7: 129-131.
4. Cristina S, Boldorini R, Brustia F, et al. Lymphoepithelioma-like carcinoma of the breast: an unusual pattern of infiltrating lobular carcinoma. Virchows Arch 2000; 437: 198-202.
5. Dadmanesh F, Peterse JL, Sapino A, et al. Lymphoepithelioma-like carcinoma of the breast: lack of evidence of Epstein-Barr virus infection. Histopathology 2001; 38: 54-61.
6. Naidoo P, Chetty R. Lymphoepithelioma-like carcinoma of the breast with associated sclerosing lymphocytic lobulitis. Arch Pathol Lab Med 2001; 125: 669-672.
7. Pes¸tereli HE, Erdogan O, Kaya R, et al. Lymphoepithelioma-like carcinoma of the breast. A newly recognized subtype of lobular carcinoma. APMIS 2002; 110: 447-450.
8. Ilvan S, Celik V, Ulker Akyildiz E, et al. Lymphoepithelioma-like carcinoma of the breast: is it a distinct entity? Clinicopathological evaluation of two cases and review of the literature. Breast 2004; 13: 522-526.
9. Sanati S, Ayala A, Middleton L. Lymphoepithelioma-like carcinoma of the breast: Report of a case mimicking lymphoma. Ann Diag Pathol 2004; 8: 309-315.
10. Kurose A, Ichinohasama R, Kanno H, et al. Lymphoepithelioma- like carcinoma of the breast. Report of a case with the first electron microscopic study and review of the literature. Virchows Arch 2005; 447: 653-659.
11. Saleh R, DaCamara P, Radhi J, et al. Lymphoepithelioma-like carcinoma of the breast mimicking nodular sclerosing Hodgkin’s lymphoma. Breast J 2005; 11: 353-354.
12. Kulka J, Kovalszky I, Svastics E, et al. Lymphoepithelioma-like carcinoma of the breast: not Epstein-Barr virus-, but human papilloma virus-positive. Hum Pathol 2008; 39: 298-301.
13. O’Sullivan-Mejia E, Idowu MO, Davis Masssey H, et al. Lymphoepithelioma-like carcinoma of the breast: diagnosis by core needle biopsy. Breast J 2009; 15: 658-660.
14. Jeong AK, Park SB, Kim YM, et al. Lymphoepithelioma-like carcinoma of the breast. J Ultrasound Med 2010; 29: 485-488.
15. Küçükzeybek BB, Bener S, Çalll AO, et al. Prognostic Significance of Bcl-2 and p53 Protein Expressions and Ki67 Proliferative Index in Diffuse Large B-cell Lymphoma. Turk J Haematol 2013; 30: 275-282.
16. Trihia H, Siatra H, Gklisty H, et al. Lymphoepithelioma-like carcinoma of the breast: cytological and histological features and review of the literature. Acta Cytologica 2012; 56: 85-91.
17. Nio Y, Tsuboi K, Tamaoki M, et al. Lymphoepithelioma like carcinoma of the breast: a case report with a special analysis of an association with human papilloma virus. Anticancer Res 2012; 32: 1435-1441.
18. Dinniwell R, Hanna WM, Mashhour M, et al. Lymphoepithelioma-like carcinoma of the breast: a diagnostic and therapeutic challenge. Curr Oncol 2012; 19: 177-183.
19. Top ÖE, Vardar E, Yagˇcl A, et al. Lymphoepithelioma-like carcinoma of the breast: a case report. Breast Health 2014; 10: 177-180.
20. Abdou AG, Asaad NY. Lymphoepithelioma-like carcinoma of the breast: cytological, histological, and immunohistochemical characteristics. Diagn Cytopathol 2015; 43: 210-213.
21. Suzuki I, Chakkabat P, Goicochea L, et al. Lymphoepithelioma-like carcinoma of the breast presenting as breast abscess. World J Clin Oncol 2014; 5: 1107-1112.
22. Jansari TR, Gupta T, Trivedi PP, et al. Lymphoepithelioma-like carcinoma of the breast: a case report. Ann Pathol Lab Med 2015; 2: C235-C238.
23. Nankin NL, Gondusky CJ, Abasolo PA, et al. Lymphoepithelioma like carcinoma of the breast. Radiol Case Rep 2015; 10: 963.
24. Herrera-Goepfert R, Caro-Sánchez C, Maafs-Molina E. Lymphoepithelioma-like carcinoma of the breast: a singular morphological pattern with an expected outcome. Austin J Clin Case Rep 2016; 3: 1102.
25. Shet T, Pai T, Shetty O, Desai S. Lymphoepithelioma-like carcinoma of breast- evaluation for Epstein-Barr virus - encoded RNA, human papillomavirus, and markers of basal cell differentiation. Ann Diagn Pathol 2016; 25: 42-47.
26. Kon S, Kasai K, Tsuzuki N, et al. Lymphoepithelioma-like carcinoma of rectum: possible relation with EBV. Pathol Res Pract 2001; 197: 577-582.
27. Yamada T, Tatsuzawa Y, Yagi S, et al. Lymphoepitheliomalike esophageal carcinoma: report of a case. Surg Today 1999; 29: 542-544.
28. Tamas EF, Nielsen ME, Schoenberg MP, et al. Lymphoepithelioma-like carcinoma of the urinary tract: a clinicopathological study of 30 pure and mixed cases. Mod Pathol 2007; 20: 828-834.
29. Blasi MA, Ventura L, Laguardia M, et al. Lymphoepithelioma-like carcinoma involving the lacrimal gland and infiltrating the eyelids. Eur J Ophthalmol 2011; 21: 320-323.
30. Bloching M, Hinze R, Berghaus A. Lymphepithelioma-like carcinoma of the lacrimal gland. Eur Arch Otorhinolaryngol 2000; 257: 399-401.
31. Andryk J, Freije JE, Schultz CJ, et al. Lymphoepithelioma of the larynx. Am J Otolaryngol 1996; 17: 61-63.
32. Lee W. Intrahepatic lymphoepithelioma-like cholangiocarcinoma not associated with Epstein-Barr virus: a case report. Case Rep Oncol 2011; 4: 68-73.
33. Nemolato S, Fanni D, Naccarato AG, et al. Lymphoepithelioma-like hepatocellular carcinoma: a case report and a review of the literature. World J Gastroenterol 2008; 14: 4694-4696.
34. Ho JC, Wong MP, Lam WK. Lymphoepithelioma-like carcinoma of the lung. Respirology 2006; 11: 539-545.
35. Krishnamurthy S, Lanier AP, Dohan P, et al. Salivary gland cancer in Alaskan natives, 1966–1980. Hum Pathol 1987; 18: 986-996.
36. Hamilton-Dutoit SJ, Therkildsen MH, Neilsen NH, et al. Undifferentiated carcinoma of the salivary gland in Greenlandic Eskimos: demonstration of Epstein–Barr virus DNA by in situ nucleic acid hybridization. Hum Pathol 1991; 22: 811-815.
37. Saemundsen AK, Albeck H, Hansen JP, et al. Epstein-Barr virus in nasopharyngeal and salivary gland carcinomas of Greenland Eskimos. Br J Cancer 1982; 46: 721-728.
38. Saw D, Lau WH, Ho JH, et al. Malignant lymphoepithelial lesion of the salivary gland. Hum Pathol 1986; 17: 914-923.
39. Kumar KL, Chayanika K, Ahmed A, et al. Lymphoepithelioma like carcinoma of orbital adnexa: A rare case report. Inter J Med Res Health Sci 2015; 4: 702-704.
40. Welch PQ, Williams SB, Foss RD, et al. Lymphoepithelioma-like carcinoma of head and neck skin: a systematic analysis of 11 cases and review of literature. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2011; 111: 78-86.
41. Herath CH, Chetty R. Epstein–Barr virus-associated lymphoepithelioma-like gastric carcinoma. Arch Pathol Lab Med 2008; 132: 706-709.
42. Nicolato A, Ferraresi P, Bontempini L, et al. Multiple brain metastases from “lymphoepithelioma-like” thymic carcinoma: a combined stereotacticradiosurgical approach. Surg Neurol 2001; 55: 232-234.
43. Shek TW, Luk IS, Ng IO, et al. Lymphoepithelioma-like carcinoma of the thyroid gland: lack of evidence of association with Epstein-Barr virus. Hum Pathol 1996; 27: 851-853.
44. Satyanarayana S, Pathak SD, Saraswat V, et al. Tracheal lymphoepithelioma-like carcinoma: a case report. Indian J Cancer 2002; 39: 112-115.
45. Terai A, Terada N, Ichioka K, et al. Lymphoepithelioma-like carcinoma of the ureter. Urology 2005; 66: 1109.
46. Porcaro AB, Gilioli E, Migliorini F, et al. Primary lymphoepithelioma-like carcinoma of the urinary bladder: report of one case with review and update of the literature after a pooled analysis of 43 patients. Int Urol Nephrol 2003; 35: 99-106.
47. Kaul R, Gupta N, Sharma J, et al. Lymphoepitheliomalike carcinoma of the uterine cervix. J Cancer Res Ther 2009; 5: 300-301.
48. McCluggage WG. Lymphoepithelioma-like carcinoma of the vagina. J Clin Pathol 2001; 54: 964-965.
49. Niu W, Heller DS, D’Cruz C. Lymphoepithelioma-like carcinoma of the vulva. J Low Genit Tract Dis 2003; 7: 184-186.
50. Slukvin II, Schink JC, Warner TF. Lymphoepithelioma-like carcinoma of the vulva: a case report. J Low Genit Tract Dis 2003; 7: 136-139.
51. Iezzoni JC, Gaffey MJ, Weiss LM. The role of Epstein-Barr Virus in lymphoepithelioma-like carcinomas. Am J Clin Pathol 1995; 103: 308-315.
52. Ribassin-Majed L, Marguet S, Lee AW, et al. What is the best treatment of locally advanced nasopharyngeal carcinoma? An individual patient data network meta-analysis. J Clin Oncol 2017; 35: 498-505.
53. Early Breast Cancer Trialists’ Collaborative Group (EBCTCG), Peto R, Davies C, Godwin J, et al. Comparisons between different polychemotherapy regimens for early breast cancer: meta-analyses of long-term outcome among 100,000 women in 123 randomised trials. Lancet 2012; 379: 432-444.
54. Ridolfi RL, Rosen PP, Port A, et al. Medullary carcinoma of the breast: a clinicopathologic study with 10 year follow-up. Cancer 1977; 40: 1365-1385.
55. Lakhani SR, Ellis IO, Schnitt SJ, et al. WHO Classification of Tumors of the Breast. In: Carcinomas with medullary features. Jacquemier J, Reis-Filho JS, Lakhani SR, Rakha E (eds). 4th ed. International Agency for Research on Cancer, Lyon 2012; 46-47.
56. Ohtani H, Mori-Shiraishi K, Nakajima M, et al. Defining lymphocyte-predominant breast cancer by the proportion of lymphocyte-rich stroma and its significance in routine histopathological diagnosis. Pathol Int 2015; 65: 644-651.

Address for correspondence

Nektarios Koufopoulos
Department of Pathology
“Saint Savvas” Anti-Cancer Hospital
13 Parnasidos street
12136 Peristeri
Athens, Greece
e-mail: koufonektar@yahoo.com
Copyright: © 2018 Polish Association of Pathologists and the Polish Branch of the International Academy of Pathology This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International (CC BY-NC-SA 4.0) License (http://creativecommons.org/licenses/by-nc-sa/4.0/), allowing third parties to copy and redistribute the material in any medium or format and to remix, transform, and build upon the material, provided the original work is properly cited and states its license.
FEATURED PRODUCTS
Quick links
© 2018 Termedia Sp. z o.o. All rights reserved.
Developed by Bentus.
PayU - płatności internetowe