Lymphoepithelioma-like breast carcinoma

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.

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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