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Available online at www.sciencedirect.com
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Lymphoepithelial-like carcinomas of the head and neck Bruce M. Wenig, MD Department of Pathology, The Icahn School of Medicine at Mount Sinai, Mount Sinai Health System, New York, New York 10003
article info
abstract
Keywords:
Lymphoepithelial-like carcinomas (LELC) of the head and neck represent malignant
Lymphoepithelial-like carcinoma
neoplasms that are histologically similar to nasopharyngeal carcinoma (NPC), nonkerati-
head and neck
nizing undifferentiated type but arise in locations other than the nasopharynx. The most
salivary glands
common location for LELC in the head and neck is the salivary glands, in particular the
Epstein-Barr virus
parotid gland. However, LELC may arise in other sites including the oropharynx (tonsils,
human papillomavirus
base of tongue), sinonasal tract, larynx, and middle ear/temporal bone. Unlike the
nasopharyngeal carcinoma
nonkeratinizing undifferentiated type of NPC which is etiologically linked to Epstein-Barr virus (EBV), LELCs are not uniformly associated with EBV. The differential diagnosis for LELC varies per site and depending on the site of occurrence may include lymphoepithelial sialadenitis, sinonasal undifferentiated carcinoma (SNUC), and large cell neuroendocrine carcinoma. Treatment general includes combined (multimodality) therapy including surgical resection, neck dissection, radiation therapy and/or chemotherapy. The prognosis may vary per site overall favorable owing to a good response to therapy. & 2015 Elsevier Inc. All rights reserved.
Introduction In the head and neck, the nasopharynx is considered the prototypic location for Epstein–Barr virus (EBV)-associated carcinomas. The World Health Organization (WHO) classification of nasopharyngeal carcinomas (NPCs) is primarily predicated on the presence or absence of keratinization and secondarily according to cell type and association with EBV.1 At present, the WHO classification of NPCs includes 2 general tumor types: (1) keratinizing squamous cell carcinoma and (2) nonkeratinizing squamous cell carcinoma, which is further subdivided into differentiated and undifferentiated subtypes, both of which have a strong association with EBV.1 The WHO classification of nasopharyngeal carcinoma also includes basaloid squamous cell carcinoma, a high-grade (non-viral) associated variant of squamous cell carcinoma.1
NPC, nonkeratinizing undifferentiated type, has in the past been referred to as lymphoepithelioma, an unfortunate and incorrect term, as this malignancy is wholly epithelial, albeit with a prominent associated benign lymphoplasmacytic cell infiltrate. Morphologically identical neoplasms to the NPC, nonkeratinizing undifferentiated type may originate in mucosal sites of the head and neck outside of the nasopharynx proper.2 The terms that have been used for such non-nasopharyngeal undifferentiated carcinomas with histologic features similar to NPC nonkeratinizing undifferentiated type include lymphoepithelial-like carcinoma, undifferentiated carcinoma with lymphoid stroma, lymphoepithelioma-like carcinoma, malignant lymphoepithelial lesion, and carcinoma ex lymphoepithelial lesion. The term lymphoepithelial-like carcinoma (LELC) will be used throughout this article.
The author has no relevant financial or commercial relationships to disclose. E-mail address: [email protected] http://dx.doi.org/10.1053/j.semdp.2014.12.004 0740-2570/& 2015 Elsevier Inc. All rights reserved.
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LELC can be defined as any carcinoma outside the nasopharynx without evidence of cellular differentiation (i.e., undifferentiated) with or without an associated nonneoplastic lymphoplasmacytic cell infiltrate that histologically is similar to NPC nonkeratinizing undifferentiated type. LELCs may or may not be associated with EBV. Further, these LELCs may show histologic similarities to other malignant neoplasms of specific sites in the head and neck creating challenges in the differential diagnosis, especially in small biopsy sampling. Given the potential differences in the treatment and biologic behavior from LELC, differentiating these site-specific malignant neoplasms is important. This article will focus on LELCs of non-nasopharyngeal mucosal sites of the head and neck, including the salivary glands, sinonasal tract, oropharynx, larynx, and middle ear/ temporal bone. For completion, it should be noted that lymphoepithelial-like carcinomas occur throughout the body; the reader is referred to other texts for a discussion of nonhead and neck lymphoepithelial-like carcinomas.
Salivary gland lymphoepithelial-like carcinoma Clinical findings The salivary glands, in particular the parotid gland, represent the most common non-nasopharyngeal location for LELCs to arise. However, salivary gland LELCs are considered uncommon tumors.3,4 In general, salivary gland LELCs occur over a wide age range, with most patients in the 5th decade of life. The most common site of occurrence is in the parotid gland (80%), followed by the submandibular gland,3,4 with rare occurrence in the sublingual gland5 and in minor salivary glands throughout the upper aerodigestive tract including the oral cavity.2,6,7 LELCs of the parotid gland often have unique ethnic and demographic features, including predilection for Arctic region natives (Eskimos/Inuits from Alaska, Canada, Greenland), Southeastern Chinese, and Japanese.3,4 The highest incidence worldwide of salivary gland LELCs is in the Eskimo/Inuit population.4 In the Eskimos/Inuit population, salivary gland LELC is more common in women, predilects to the parotid gland, and has a more aggressive clinical course presents with higher clinical stage disease as compared to similar tumors occurring in other populations.4,8 The clinical presentation of LELC is usually that of a mass swelling with or without associated pain and/or facial nerve paralysis. In addition, there is a high frequency (10–40%) of concurrent cervical lymphadenopathy. In advanced tumors, fixation to skin and/or underlying structures may be present. Most LELCs develop de novo, but some may arise in association with lymphoepithelial sialadenitis (LESA).9 However, such “transformation” remains questionable, with the possibility that the presence of LESA in foci adjacent to LELC represents a reactive process and not a precursor lesion. There is no known association with other autoimmune disorders (e.g., Sjögren disease).
Etiology Salivary gland LELCs are linked to Epstein–Barr virus (EBV). Near 100% of LELCs in patients from endemic areas are
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associated with EBV.4,8,10–18 The presence of EBV in clonal episomal form suggests a role in tumor development. Elevated serologic titers of anti-EBV viral capsid antigen IgA and anti-EBV nuclear antigen IgG are seen in the majority of patients from endemic areas. In non-endemic areas, EBV is usually absent but may rarely be identified.4,19–22 The absence of EBV does not exclude the diagnosis.
Pathology Grossly, LELCs tend to be circumscribed but unencapsulated, lobulated, firm, tan–white masses measuring from 1 to 10 cm in greatest dimension. The histologic features include an infiltrative tumor characterized by the presence of lobules, sheets, nests, islands, trabeculae, or cords of neoplastic cells separated by or overrun by lymphoid stroma (Fig. 1). The neoplastic cells are polygonal to spindle-shaped with large round to oval, basophilic to vesicular-appearing nuclei, one or more prominent nucleoli, and abundant amphophilic to lightly eosinophilic cytoplasm (Fig. 1). The cells have indistinct cell borders and syncytial growth is usually evident. Moderate to marked nuclear pleomorphism, as well as increased mitotic activity and necrosis often are present. Focal squamous differentiation may be identified. In association with the carcinoma, a dense nonneoplastic lymphoplasmacytic cell infiltrate, with or without germinal centers, is commonly present. The lymphoplasmacytic cell infiltrate is usually identified between and around tumor nests or may overrun and obscure the carcinomatous component (Fig. 1). The presence of abundant histiocytes may be seen creating a “starry sky” appearance. Additional findings may include the presence of noncaseating granulomatous inflammation and an amyloid stroma. In some cases, especially those identified in Inuit population, a prominent basaloid morphology may be seen (Fig. 1).23 Such tumors have been referred to as basaloid LELCs and are also associated with EBV. In all cases, invasion is present, including into nonneoplastic salivary gland parenchyma, surrounding connective tissues, neurotropism, and/or angioinvasion.
Immunohistochemistry and molecular analysis The epithelial cells are reactive for cytokeratins (Fig. 2) and epithelial membrane antigen (EMA). Variable p63 reactivity is present from case to case and even within the same case, ranging from diffuse to focal reactivity (Fig. 2). c-Kit (CD117) reactivity may be present, but p16 is negative. In situ hybridization for Epstein–Barr encoded RNA (EBER) is consistently positive in cases from endemic regions irrespective of cell type (Fig. 2). In non-endemic populations, EBER is usually negative but may be positive. The lymphoid cells show reactivity for both B-cell (CD20) and T-cell (CD3) markers.
Treatment and prognosis The treatment for parotid gland LELC includes combined (multimodality) therapy including surgical resection, neck dissection, and radiation therapy.24 Up to 40% of patients may present with regional lymph node metastasis, thereby
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Fig. 1 – Lymphoepithelial-like carcinoma of the parotid gland. (A and B) Infiltrative but circumscribed cellular proliferation separated from the adjacent parotid gland parenchyma (left); the proliferation includes clusters of lighter-staining neoplastic foci in a background of dense lymphocytic cell infiltrate including germinal centers. Note the absence of an associated desmoplastic reaction to the infiltrative neoplasm. (C and D) Cohesive cluster of neoplastic cells characterized by cells with enlarged vesicular nuclei, prominent eosinophilic nucleoli, and indistinct borders creating a syncytial growth. These histologic features are similar to nasopharyngeal carcinoma nonkeratinizing undifferentiated type. Variant histologic features may include (E) fascicular growth with spindle-shaped neoplastic cells and (F) basaloid cell features.
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Fig. 2 – Lymphoepithelial-like carcinoma of the parotid gland. The lesional cells are (A) cytokeratin positive and (B) p63 positive (nuclear staining). In situ hybridization for Epstein–Barr encoded RNA (EBER) is positive irrespective of the cytomorphologic features, including (C) epithelioid cells, (D) spindle-shaped cells, and (E) basaloid cells. necessitating neck dissection.4 Local recurrence and distant metastasis may occur. The 3-year locoregional control (LRC), progression-free survival (PFS), and overall survival (OS) rates
were reported to be 94%, 92%, and 93%, respectively. The 5year survival rate for parotid gland LELC was reported to be as high as 86%.24
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Differential diagnosis Metastasis to the parotid gland from an EBV-associated nasopharyngeal carcinoma (NPC) should be considered and excluded prior to rendering a diagnosis of primary parotid gland LELC. It is not uncommon for NPCs to metastasize as occult primary carcinomas. LELCs share overlapping histologic and immunohistochemical findings to their nasopharyngeal counterparts. Differentiation is predicated on detailed clinical evaluation to exclude primary nasopharyngeal carcinoma. The absence of EBER, especially in a patient with parotid gland LELC, can be used in conjunction with clinical and radiologic findings to support a diagnosis of primary parotid LELC from NPC, as the latter is usually but not always EBER positive. Given the presence of the relatively recently described oropharyngeal human papillomavirus (HPV)-associated LELC25,26 (see below), it would be prudent to perform p16 staining in any carcinoma, including those of salivary glands, with histologic features of LELC that are negative for EBV to exclude a possible metastasis from a primary oropharyngeal LELC. Similar to the EBV-associated NPCs, oropharyngeal HPV-associated carcinomas may metastasize to cervical neck lymph nodes in the absence of a known primary carcinoma. In those cases of LELC that are EBER negative, the absence of p16 confirmed by the absence of high-risk HPV by molecular testing (e.g., in situ hybridization or polymerase chain reaction) allows for differentiation from a metastatic oropharyngeal HPV-associated carcinoma. The differential diagnosis also includes malignant lymphoma and malignant melanoma, but the presence of consistent and strong cytokeratin immunoreactivity and the absence of hematolymphoid markers (CD45, CD20, and others) and melanoma-related markers (S100 protein, HMB45, SOX10, melan A, tyrosinase, and MITF1) differentiate LELC from these other diagnostic considerations. The presence of overtly malignant cells differentiates LELC from lymphoepithelial sialadenitis. The histologic setting is
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similar to that of benign lymphoepithelial lesion except for the presence of a malignant epithelial component instead of a benign epithelial component. Transformation of a benign lymphoepithelial lesion to a malignant epithelial neoplasm (so-called malignant lymphoepithelial lesion) occurs much less frequently than transformation to malignant lymphoma. Although LELCs of salivary glands are rare tumors, these carcinomas most likely develop as de novo neoplasms unrelated to other conditions (e.g., lymphoepithelial sialadenitis). There is an increased incidence of malignant lymphoepithelial lesions among Eskimos in whom it is more common in men than in women and most frequently occurs in the 5th decade of life. Among Eskimos, the parotid gland is the most frequent site of occurrence; among Asians, the submandibular gland is most often involved. The histologic picture of carcinomatous component ranges from low to high grade. There is some evidence linking EBV with this neoplasm, but there is equal evidence showing an absence of EBV DNA in these neoplasms. Another entity to consider in the differential diagnosis from LELC is the rarely occurring primary salivary gland large cell undifferentiated carcinoma (LCUC), which is a high-grade malignant epithelial salivary gland tumor lacking evidence of glandular, squamous, or neuroendocrine differentiation and an inability to be classified in another (more specific) salivary gland carcinoma. In contrast to LELC, LCUC is a tumor of adults with patients usually in 7th–8th decades of life.27–31 There is no ethnic or racial predilection or association with EBV. The majority occur in the parotid gland, although submandibular gland, lacrimal gland, and minor salivary glands may rarely be primary sites of occurrence. The presentation is usually that of a rapidly enlarging mass, often with associated facial nerve paralysis and cervical lymphadenopathy; fixation to adjacent tissues is commonly present. The lesional cells in LCUC are large (usually measuring greater than 3 times the size of cells in small cell neuroendocrine carcinoma), polygonal with enlarged round to oval vesicular nuclei, one or more prominent nucleoli, abundant
Fig. 3 – Large cell undifferentiated carcinoma of the parotid gland. (A) Intraparotid infiltrative neoplasm appearing composed of markedly enlarged cells with pleomorphic round to oval nuclei with vesicular nuclear chromatin, prominent eosinophilic nucleoli, and indistinct eosinophilic cytoplasm. (B) The lesional cells are only reactive for cytokeratins in this example OSCAR. The cytomorphologic features coupled to absence of cellular differentiation and absence of EBER (not shown) allows for a diagnosis of large cell undifferentiated carcinoma and differentiation from other lesions, including lymphoepithelial-like carcinoma.
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amphophilic to eosinophilic cytoplasm, and rather distinct cell borders (Fig. 3). Marked nuclear pleomorphism is commonly seen but occasional cases may display nuclear uniformity. There is increased mitotic activity including atypical mitoses and tumor necrosis commonly identified. Multinucleated (osteoclast-like) giant cells may be identified. Invasion is readily apparent, including into nonneoplastic salivary gland parenchyma, surrounding connective tissues, perineural invasion, and lymphovascular invasion. A benign lymphoplasmacytic cell infiltrate may be present but does not approach the density and/ or extent seen in lymphoepithelial carcinoma. Immunohistochemical staining shows the lesional cells to be cytokeratin positive. Markers for EBV and HPV are invariably absent. Melanocytic, hematolymphoid, and mesenchymal markers are negative. Staining for neuroendocrine markers (e.g., synaptophysin) is negative and should be performed to exclude a possible diagnosis of the large cell type of neuroendocrine carcinoma. LCUCs are aggressively behaving tumors, with high rate of recurrence and metastases (regional and distant) with poor prognosis, including a 36% 2-year survival.25,32
Oropharyngeal lymphoepithelial-like carcinoma Clinical findings In 2010, Singhi et al.25 described a nonkeratinizing (lymphoepithelial-like) undifferentiated carcinoma of the oropharynx associated with human papillomavirus (HPV), thereby, representing a morphologic variant of HPV-related head and neck cancer.26 In terms of their anatomic localization, more than 90% occur in the tonsils and base of tongue and tend to occur in patients below 60 years of age and in nonsmokers. Symptoms may include oropharyngeal mass and/or neck mass and cervical lymph node involvement occurs in approximately 70% of cases at presentation. Oropharyngeal HPV-associated carcinomas including LELCs may metastasize as occult primary carcinomas.
Pathology The histomorphologic features of the oropharyngeal LELCs are similar to their nasopharyngeal counterparts, including the presence of lobules, sheets, nests, or cords of neoplastic cells separated by or overrun by lymphoid stroma (Fig. 4). The neoplastic cells include large round to oval nuclei with vesicular-appearing chromatin, one or more prominent nucleoli, and abundant amphophilic to lightly eosinophilic cytoplasm (Fig. 4). In association with the carcinoma, a dense nonneoplastic lymphoplasmacytic cell infiltrate is commonly present, identified in and around tumor nests, but may overrun and obscure the carcinomatous component.
Immunohistochemistry and molecular analysis The lesional cells are immunoreactive for cytokeratins and p16, the latter in greater than 70% of lesional cells, including nuclear and cytoplasmic staining (Fig. 4); EBER staining is negative. Molecular analysis (e.g., in situ hybridization and polymerase chain reaction) shows the presence of transcriptionally active virus in the majority of cases.
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Treatment and prognosis Oropharyngeal LELCs are radiosensitive cancers and as a result the disease-specific survival is good, comparable to those associated with HPV-related oropharyngeal squamous cell carcinoma and better than that of HPV-negative carcinomas.27
Differential diagnosis Primary nasopharyngeal EBV-associated carcinoma (nonkeratinizing undifferentiated type) and primary oropharyngeal HPV-associated LELC may present as lymph node metastases in the absence of a known primary cancer. Differentiation of these 2 tumor types and therefore determination of the primary site of origin would be based on the presence or absence of EBV and HPV. Given the identical histologic features shared by primary nasopharyngeal EBV-associated carcinoma (nonkeratinizing undifferentiated type) and primary oropharyngeal HPV-associated LELC, when confronted with cervical lymph node metastasis without a known primary cancer in which the tumor is an undifferentiated carcinoma (cytokeratin positive), the work up should include evaluation for both EBV and HPV. The differential diagnosis also includes malignant lymphoma and malignant melanoma, but the presence of consistent and strong cytokeratin immunoreactivity and the absence of hematolymphoid markers (CD45, CD20, and others) and melanoma-related markers (S100 protein, HMB45, SOX10, melan A, tyrosinase, and MITF1) differentiate LELC from these other diagnostic considerations.
Sinonasal tract lymphoepithelial-like carcinoma Clinical findings Rare examples of sinonasal tract carcinomas morphologically similar to their histologic counterparts in the nasopharynx have been described.2,33,34 The sinonasal LELCs primarily affect men in the 5th–7th decades of life. Sinonasal LELCs more commonly occur in the nasal cavity than the paranasal sinuses. The clinical presentation includes nasal obstruction, epistaxis and, in the presence of invasive growth, proptosis, and cranial nerve palsies.
Etiology Similar to its nasopharyngeal counterpart, there is a strong association with EBV,2,33,34 but not all cases are EBV positive.2
Pathology The histologic findings include the presence of a submucosal infiltrative neoplastic proliferation characterized by varying growth patterns, including trabeculae, cords, islands, lobules, and sheets, often without a desmoplastic stromal reaction (Fig. 5). The neoplastic cells include large round to oval nuclei with vesicular-appearing chromatin, one or more prominent nucleoli, and abundant amphophilic to lightly eosinophilic cytoplasm (Fig. 5). Indistinct cell borders result in syncytial
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Fig. 4 – Lymphoepithelial-like carcinoma of the oropharynx. (A) Submucosal clusters of lesional cells with associated dense lymphoplasmacytic cell infiltrate and absence of stromal desmoplastic reaction. (B) Histomorphologic features are similar to those of EBV-associated nasopharyngeal carcinoma nonkeratinizing undifferentiated type, including cells with enlarged pleomorphic and vesicular nuclei and prominent nucleoli. Lesional cells are (C) cytokeratin positive and (D) p16 positive. EBER staining was negative (not shown). Subsequent evaluation by polymerase chain reaction confirmed the presence of high-risk human papillomavirus (not shown). This carcinoma can metastasize to cervical neck lymph nodes as an occult primary carcinoma. In such a scenario, purely based on the light microscopic features, a primary (EBV-associated) nasopharyngeal carcinoma would be the most likely consideration. EBER staining would be negative and unless consideration was given for a possible oropharyngeal origin, p16 staining which would be diagnostic might not be ordered. appearance. Nuclear pleomorphism is present, but generally there is an absence of increased mitotic activity. Necrosis is uncommon but may be present including central comedotype. Keratinization is usually not evident. In association with the carcinoma, a dense nonneoplastic lymphoplasmacytic cell infiltrate is commonly present but is typically less prominent as compared to nasopharyngeal carcinoma.
Immunohistochemistry and molecular analysis The lesional cells are cytokeratin positive and are strongly EBER positive (Fig. 5). There is an absence of immunoreactivity for hematolymphoid markers, melanoma-related markers, and neuroendocrine/neuroectodermal markers. P16 staining is absent.
Treatment and prognosis Treatment of sinonasal LELCs includes surgery combined with radiotherapy or chemoradiation.2 The prognosis is favorable owing to a good response to local radiotherapy. Regional cervical lymph node metastasis may be seen at presentation. The favorable prognosis is not altered even in the presence of nodal metastasis. The mortality rate of adequately treated LELC patients is low.2
Differential diagnosis In the sinonasal tract, a more common malignant undifferentiated neoplasm that is cytokeratin positive is the sinonasal
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Fig. 5 – Sinonasal lymphoepithelial-like carcinoma. (A) Polypoid invasive lesion with broad interconnecting cords of tumor similar to the growth pattern seen in sinonasal nonkeratinizing carcinoma. (B) The lesional cells are epithelioid and spindleshaped. (C) Both cell types (epithelioid shown here) are comprised of enlarged vesicular nuclei and prominent eosinophilic nuclei. Increased mitotic activity is present. (D) A focus of central comedotype necrosis is present. Lesional cells are immunoreactive for (E) cytokeratin (AE1/AE3) and (F) in situ hybridization for Epstein–Barr encoded RNA (EBER).
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undifferentiated carcinoma (SNUC), a highly aggressive and clinicopathologically distinctive carcinoma of uncertain histogenesis that typically presents with locally extensive disease and by definition lacks evidence of any type of cellular differentiation, including squamous, glandular, and neuroendocrine/neuroectodermal (e.g., neurofibrillary material and neural rosettes).35 SNUCs are more common in men than in women and tend occur over a wide age range, including 3rd–9th decades of life, with a median at presentation in the 6th decade. Typically, patients present with multiple symptoms that include nasal obstruction, epistaxis, proptosis, visual disturbances (e.g., diplopia), facial pain, and symptoms of cranial nerve involvement. A rather characteristic clinical phenomenon is the development of symptoms over relatively short duration (weeks to months). Further, at presentation, SNUCs often are extensively infiltrative, involving multiple sites, including the nasal cavity, one or more paranasal sinuses, orbit, skull base, and the brain. Most patients have unilateral disease but bilateral disease may occur. SNUC is a tumor of uncertain histogenesis. Although not definitively proven, given the presence in some examples of intraepithelial dysplasia/carcinoma in situ, it seems reasonable to consider that SNUCs arise from the Schneiderian epithelium and, therefore, are of ectodermal derivation. There are no known etiologic agents. SNUCs are typically negative for EBV in patients from Western populations,36,37 although EBV RNA has been identified in patients from Asian populations.36 Human papillomavirus (HPV) by p16 immunohistochemistry has been identified in a limited number of SNUCs,38,39 rarely with identification of transcriptionally active virus.39 It remains uncertain whether there is a relationship between HPV and SNUCs. SNUCs are characterized by hypercellular proliferation with varied growth, including trabecular, sheet-like, ribbons, solid, lobular, and organoid patterns. The cellular infiltrate consists of polygonal cells composed of medium- to large-sized, round to oval, hyperchromatic to vesicular nuclei, inconspicuous to prominent nucleoli, and a varying amount of eosinophilicappearing cytoplasm with poorly defined cell membranes, although distinct cell borders may be present; occasionally, cells with clear cytoplasm can be identified. There is increased mitotic activity, including atypical mitoses, and tumor necrosis (confluent areas and individual cells) is often present. SNUCs are extensively infiltrative, effacing the normal architecture of the sinonasal submucosa, and may include the presence of neurotropism, angioinvasion, and invasion of soft tissues (e.g., bone and other). Further, the brain may also be involved, representing evidence of invasion into the central nervous system. SNUCs are consistently immunoreactive with epithelial markers, including pankeratins and simple keratins (i.e., CK 7, CK8, and CK19); reactivity for pankeratins is often intense and diffuse. Variable reactivity can be identified for p63, including some cases with scattered focal positive staining, some cases completely negative, and less common diffuse p63 positivity. Focal reactivity for synaptophysin, chromogranin, CD56, and CD57 (Leu-7) may be seen. Mesenchymal, hematolymphoid, and melanoma-related markers are absent. The majority of cases are negative for EBV, but as previously indicated, there are reports of EBV identified in
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patients with SNUC. More likely, such EBV-positive SNUCs are sinonasal lymphoepithelial-like carcinomas,37 given differences in the response to treatment and in prognosis between SNUCs and sinonasal LELCs. Also as previously indicated, HPV (by p16 immunohistochemistry and molecular analysis) has been identified in a limited number of SNUCs, but it remains uncertain whether there is a relationship between HPV and SNUCs. Further, HPV-positive SNUCs may benefit from improved survival, but this finding requires further substantiation. For SNUCs, multimodality therapy is considered the best treatment approach to provide the best chance for survival and includes radical surgery and postoperative chemoradiotherapy. Generally, SNUCs are considered highly aggressive neoplasms with poor survival. Local recurrence is common and is the major cause of morbidity and mortality. Metastatic spread occurs to the bone, brain, liver, and cervical lymph nodes. The causes of death primarily relate to distant metastases. Another sinonasal tract malignant neoplasm that may be histologically undifferentiated and associated with EBV is the extranodal NK/T cell lymphoma and nasal type. However, the light microscopic features and immunoreactivity for CD3 (cytoplasmic), CD56, cytotoxic granules markers (e.g., granzyme B, cytotoxic granule-associated TIA-1, and perforin), and absence of cytokeratin allows for differentiation from sinonasal LELC.
Laryngeal lymphoepithelial-like carcinoma Clinical findings Rare examples of LELC have been reported in the larynx.40–45 These tumors are more common in men than in women and most frequently occur in older ages (7th decade or later of life). In the larynx, LELCs are more common in Caucasian populations than in Asian populations. Symptoms include hoarseness and a neck mass and less often, sore throat, dysphagia, hemoptysis, and otalgia. There is a tendency for these tumors to occur in the supraglottic larynx. Risk factors for the development of this carcinoma may include excessive use of tobacco and alcohol.43 Laryngeal LELCs are rarely associated with EBV.41,44,46
Pathology The histology of laryngeal LELCs is similar to its more common nasopharyngeal counterpart, including aggregates or syncytia of neoplastic cells characterized by enlarged vesicular nuclei and prominent nucleoli. Intraepithelial dysplasia and/or foci of squamous cell differentiation, including abrupt keratinization of conventional foci of squamous cell carcinoma, can be seen. A prominent benign lymphocytic cell infiltrate is present; a variable amount of plasma cell may be present.
Immunohistochemistry and molecular analysis The lesional cells are immunoreactive for cytokeratins. EBER is typically negative. There is an absence of immunoreactivity for neuroendocrine markers and melanoma-related markers.
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Treatment and prognosis Treatment varies and has including limited to radical surgery with adjuvant therapy (radiation and chemotherapy). Cervical nodal metastases occur in nearly 75% of patients; distant metastases, including to the lung, liver, bone, and skin, occur in approximately 25% of patients.41 Nearly one-third of patients reported death due to disease at a 21-month median follow-up.41
Differential diagnosis In the larynx, particularly the supraglottic larynx, the differential diagnosis includes laryngeal large cell neuroendocrine carcinoma (LCNEC), a relatively recently identified distinct subtype of poorly differentiated neuroendocrine carcinoma.47,48 The criteria for diagnosis of LCNEC include (1) the presence of features of neuroendocrine differentiation,
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including organoid nesting, trabecular growth, rosettes, and peripheral palisading; (2) the presence of enlarged tumor cells with vesicular chromatin, small to prominent nucleoli, and moderate to abundant cytoplasm; (3) increased mitotic activity [greater than 10 mitoses per 10 high-power fields (2 mm2)]; and (4) confirmation of neuroendocrine differentiation using immunohistochemical staining for chromogranin, synaptophysin, neuron-specific enolase, and/or neural cell adhesion molecule.48 The presence of neuroendocrine differentiation by light microscopic and immunohistochemical staining provide the means for differentiating LELC from LCNEC. Differentiation of LCNEC from LELC is important as the treatment and prognosis markedly varies. The treatment for LCNEC includes chemoradiotherapy. Commonly, patients with LCNEC present with advanced-stage clinical disease (stages III and IV), including locoregional metastases to cervical lymph nodes and distant visceral metastases (e.g., liver and other).48 The 5-year disease-specific survival (DSS) rate is reported to be 15–21%.48
Fig. 6 – Primary middle ear lymphoepithelial-like carcinoma. (A) Polypoid lesion that originated from the middle ear with dense submucosal lymphoid proliferation obscuring an infiltrative neoplasm (arrows). (B) At higher magnification epithelioid and spindle-shaped cells with enlarged vesicular nuclei and prominent eosinophilic nuclei are identified. (C) Lesional cells are immunoreactive for cytokeratin (AE1/AE3). (D) In situ hybridization for Epstein–Barr encoded RNA (EBER).
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Primary LELC of the middle ear and temporal bone In addition to the aforementioned sites of occurrence, LELCs may rarely originate in other head and neck sites. A rare site of occurrence includes the middle ear mucosa.49–52 Primary LELC arising in the middle ear is rare, with only 6 cases reported in the literature.49–52 All of these cases were reported in adult patients and all (100%) of these reported cases were associated with EBV, regardless of the age, gender, or nationality of the affected individual. Of interest is the fact that of the 6 reported cases, 4 were from the Guangdong province of China and 1 was a Filipino; the nationality of the remaining patient was not indicated. All of the patients had a history of long-standing otitis media and symptoms included hearing loss, aural fullness, or pressure sensation with or without discharge, pain, and cranial nerve palsies. Otoscopic examination findings were similar in all the cases, including the presence of polypoid granulation tissue-like mass in the middle ear cavity extending to external auditory canal. Clinical and radiologic evaluation showed the tumors limited to the middle ear/temporal bone albeit with extension to the external canal but no evidence of nasopharyngeal involvement and/or tracking of tumor from the nasopharynx to the middle ear via the eustacian tube. The histopathological findings may include the presence of a polypoid-appearing lesion with clusters or syncytia of epithelial cells with associated lymphoplasmacyticappearing infiltrate overrunning and/or obscuring the lesional cells (Fig. 6). The lesional cells are round to oval to spindle-shaped with vesicular-appearing nuclei and enlarged nucleoli (Fig. 6). Nuclear pleomorphism is present, but generally there is an absence of increased mitotic activity and necrosis. In spite of the infiltrative nature of the neoplasm, there may be an absence of an associated desmoplastic stromal reaction. Intact surface flattened to cuboidal (middle ear) epithelium may be present.
Immunohistochemistry and molecular analysis The lesional cells are immunoreactive for cytokeratins and EBER (Fig. 6).
Treatment and prognosis The optimal treatment modality remains unclear. From the limited available data, surgery and postoperative radiotherapy are considered appropriate therapeutic modalities.
Differential diagnosis The absence of an associated desmoplastic stromal reaction and presence of obscuring lymphoplasmacytic infiltrate may result in overlooking the lesional cells and a misdiagnosis. Given the presence of a polypoid lesion with associated dense lymphoplasmacytic cell infiltrate, consideration may be given to a diagnosis of a middle ear otic or aural polyp, a lesion predominantly occurring in children. Alternatively, a diagnosis of nonspecific chronic otitis media may be rendered, especially given the clinical presentation of long-standing otitis media. Close attention to the histologic findings,
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including clusters of lesional cells with enlarge vesicular nuclei and prominent nucleoli should allow for consideration of the rare diagnosis of middle ear LELC.
Conclusion Lymphoepithelial-like carcinomas of the head and neck are histologically similar to nasopharyngeal carcinoma nonkeratinizing undifferentiated type but by definition arise in mucosal sites other than the nasopharynx. LELCs are an uncommon but well-recognized entity. Similar to their nasopharyngeal counterparts, the majority of lymphoepitheliallike carcinomas in other head and neck sites are associated with Epstein–Barr virus. However, for carcinomas of the head and neck that exhibit lymphoepithelial features, an EBVdriven process by morphology alone cannot be assumed. HPV testing has disclosed a morphologic variant of HPVassociated carcinoma in the oropharynx that is histologically indistinguishable from the EBV-related carcinoma. Treatment of LELCs largely consists of surgery, combined with radiotherapy or chemoradiation. Although local spread or nodal metastases are fairly common at the time of diagnosis, the mortality rate of adequately treated LELC patients appears to be low.
re fe r en ces
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28. Hui KK, Luna MA, Batsakis JG, Ordónez NG, Weber R. Undifferentiated carcinomas of the major salivary glands. Oral Surg Oral Med Oral Pathol. 1990;69:76–83. 29. Batsakis JG, Luna MA. Undifferentiated carcinomas of salivary glands. Ann Otol Rhinol Laryngol. 1991;100:82–84. 30. Sheen TS, Tsai CC, Ko JY, Chang YL, Hsu MM. Undifferentiated carcinoma of major salivary glands. Cancer. 1997;80:357–363. 31. Hatta C, Terada T, Okita J, Kakibuchi M, Kubota A, Sakagami M. Clinicopathological study of undifferentiated carcinoma of the parotid gland. Auris Nasus Larynx. 2003;30: 273–277. 32. Airoldi M, Gabriele AM, Gabriele P, et al. Concomitant chemoradiotherapy followed by adjuvant chemotherapy in parotid gland undifferentiated carcinoma. Tumori. 2001;87: 14–17. 33. Leung SY, Yuen ST, Chung LP, et al. Epstein–Barr virus is present in a wide histological spectrum of sinonasal carcinomas. Am J Surg Pathol. 1995;19:994–1001. 34. Zong Y, Liu K, Zhong B, et al. Epstein–Barr virus infection of sinonasal lymphoepithelial carcinoma in Guangzhou. Chin Med J (Engl). 2001;114:132–136. 35. Frierson HF Jr. Sinonasal undifferentiated carcinoma. In: Barnes L, Eveson JW, Reichart P, Sidransky D, et al., eds. World Health Organization Classification of Tumours. Pathology and Genetics of Head and Neck Tumours. Lyon, France: IARC Press; 2005. 19. 36. Lopategui JR, Gaffey MJ, Frierson HF Jr, et al. Detection of Epstein–Barr viral RNA in sinonasal undifferentiated carcinoma from Western and Asian patients. Am J Surg Pathol. 1994;18:391–398. 37. Cerilli LA, Holst VA, Brandwein MS, Stoler MH, Mills SE. Sinonasal undifferentiated carcinoma: immunohistochemical profile and lack of EBV association. Am J Surg Pathol. 2001;25:156–163. 38. Wadsworth B, Bumpous JM, Martin AW, Nowacki MR, Jenson AB, Farghaly H. Expression of p16 in sinonasal undifferentiated carcinoma (SNUC) without associated human papillomavirus (HPV). Head Neck Pathol. 2011;5:349–354. 39. Bishop JA, Guo TW, Smith DF, et al. Human papillomavirusrelated carcinomas of the sinonasal tract. Am J Surg Pathol. 2013;37:185–192. 40. Micheau C, Luboinski B, Schwaab G, Richard J, Cachin Y. Lymphoepitheliomas of the larynx (undifferentiated carcinomas of nasopharyngeal type). Clin Otolaryngol Allied Sci. 1979;4:43–48. 41. Macmillan C, Kapadia SB, Finkelstein SD, Nalesnik MA, Barnes L. Lymphoepithelial carcinoma of the larynx and hypopharynx: study of eight cases with relationship to Epstein–Barr virus and p53 gene alterations, and review of the literature. Hum Pathol. 1996;27:1172–1179. 42. Ferlito A, Weiss LM, Rinaldo A, et al. Clinicopathological consultation. Lymphoepithelial carcinoma of the larynx hypopharynx, and trachea. Ann Otol Rhinol Laryngol. 1997;106:437–444. 43. Dray T, Vargas H, Weidner N, Sofferman RA. Lymphoepitheliomas of the laryngohypopharynx. Am J Otolaryngol. 1998;19:263–266. 44. Marioni G, Mariuzzi L, Gaio E, Portaleone S, Pertoldi B, Staffieri A. Lymphoepithelial carcinoma of the larynx. Acta Otolaryngol. 2002;122:429–434. 45. Coskun BU, Cinar U, Sener BM, Dadas B. Lymphoepithelial carcinoma of the larynx. Auris Nasus Larynx. 2005;32: 189–193. 46. Tsang WYW, Chan JKC. Lymphoepithelial carcinoma. In: Barnes L, Eveson JW, Reichart P, Sidransky D, et al., eds. World Health Organization Classification of Tumours. Pathology and genetics of head and neck tumours. Lyon, France: IARC Press; 2005. 132.
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50. Clark MP, Westerberg BD, Berean KW. Primary middle ear Epstein–Barr virus related lymphoepithelial carcinoma: case reports and systematic review. Laryngoscope. 2010;120: 172–177. 51. Huon LK, Wang PC, Huang SH. Epstein–Barr virus associated lymphoepithelial carcinoma in the middle ear. Otolaryngol Head Neck Surg. 2011;144:296–297. 52. Balakrishna J, Manolides S, Khorsandi A, Wenig BM. Epstein– Barr virus (EBV)-associated primary lymphoepithelial-like carcinoma of the middle ear—report of a case with review of literature. 2015. [Submitted].
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Available online at www.sciencedirect.com
www.elsevier.com/locate/semdp
Lymphoepithelial-like carcinomas of the head and neck Bruce M. Wenig, MD Department of Pathology, The Icahn School of Medicine at Mount Sinai, Mount Sinai Health System, New York, New York 10003
article info
abstract
Keywords:
Lymphoepithelial-like carcinomas (LELC) of the head and neck represent malignant
Lymphoepithelial-like carcinoma
neoplasms that are histologically similar to nasopharyngeal carcinoma (NPC), nonkerati-
head and neck
nizing undifferentiated type but arise in locations other than the nasopharynx. The most
salivary glands
common location for LELC in the head and neck is the salivary glands, in particular the
Epstein-Barr virus
parotid gland. However, LELC may arise in other sites including the oropharynx (tonsils,
human papillomavirus
base of tongue), sinonasal tract, larynx, and middle ear/temporal bone. Unlike the
nasopharyngeal carcinoma
nonkeratinizing undifferentiated type of NPC which is etiologically linked to Epstein-Barr virus (EBV), LELCs are not uniformly associated with EBV. The differential diagnosis for LELC varies per site and depending on the site of occurrence may include lymphoepithelial sialadenitis, sinonasal undifferentiated carcinoma (SNUC), and large cell neuroendocrine carcinoma. Treatment general includes combined (multimodality) therapy including surgical resection, neck dissection, radiation therapy and/or chemotherapy. The prognosis may vary per site overall favorable owing to a good response to therapy. & 2015 Elsevier Inc. All rights reserved.
Introduction In the head and neck, the nasopharynx is considered the prototypic location for Epstein–Barr virus (EBV)-associated carcinomas. The World Health Organization (WHO) classification of nasopharyngeal carcinomas (NPCs) is primarily predicated on the presence or absence of keratinization and secondarily according to cell type and association with EBV.1 At present, the WHO classification of NPCs includes 2 general tumor types: (1) keratinizing squamous cell carcinoma and (2) nonkeratinizing squamous cell carcinoma, which is further subdivided into differentiated and undifferentiated subtypes, both of which have a strong association with EBV.1 The WHO classification of nasopharyngeal carcinoma also includes basaloid squamous cell carcinoma, a high-grade (non-viral) associated variant of squamous cell carcinoma.1
NPC, nonkeratinizing undifferentiated type, has in the past been referred to as lymphoepithelioma, an unfortunate and incorrect term, as this malignancy is wholly epithelial, albeit with a prominent associated benign lymphoplasmacytic cell infiltrate. Morphologically identical neoplasms to the NPC, nonkeratinizing undifferentiated type may originate in mucosal sites of the head and neck outside of the nasopharynx proper.2 The terms that have been used for such non-nasopharyngeal undifferentiated carcinomas with histologic features similar to NPC nonkeratinizing undifferentiated type include lymphoepithelial-like carcinoma, undifferentiated carcinoma with lymphoid stroma, lymphoepithelioma-like carcinoma, malignant lymphoepithelial lesion, and carcinoma ex lymphoepithelial lesion. The term lymphoepithelial-like carcinoma (LELC) will be used throughout this article.
The author has no relevant financial or commercial relationships to disclose. E-mail address: [email protected] http://dx.doi.org/10.1053/j.semdp.2014.12.004 0740-2570/& 2015 Elsevier Inc. All rights reserved.
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LELC can be defined as any carcinoma outside the nasopharynx without evidence of cellular differentiation (i.e., undifferentiated) with or without an associated nonneoplastic lymphoplasmacytic cell infiltrate that histologically is similar to NPC nonkeratinizing undifferentiated type. LELCs may or may not be associated with EBV. Further, these LELCs may show histologic similarities to other malignant neoplasms of specific sites in the head and neck creating challenges in the differential diagnosis, especially in small biopsy sampling. Given the potential differences in the treatment and biologic behavior from LELC, differentiating these site-specific malignant neoplasms is important. This article will focus on LELCs of non-nasopharyngeal mucosal sites of the head and neck, including the salivary glands, sinonasal tract, oropharynx, larynx, and middle ear/ temporal bone. For completion, it should be noted that lymphoepithelial-like carcinomas occur throughout the body; the reader is referred to other texts for a discussion of nonhead and neck lymphoepithelial-like carcinomas.
Salivary gland lymphoepithelial-like carcinoma Clinical findings The salivary glands, in particular the parotid gland, represent the most common non-nasopharyngeal location for LELCs to arise. However, salivary gland LELCs are considered uncommon tumors.3,4 In general, salivary gland LELCs occur over a wide age range, with most patients in the 5th decade of life. The most common site of occurrence is in the parotid gland (80%), followed by the submandibular gland,3,4 with rare occurrence in the sublingual gland5 and in minor salivary glands throughout the upper aerodigestive tract including the oral cavity.2,6,7 LELCs of the parotid gland often have unique ethnic and demographic features, including predilection for Arctic region natives (Eskimos/Inuits from Alaska, Canada, Greenland), Southeastern Chinese, and Japanese.3,4 The highest incidence worldwide of salivary gland LELCs is in the Eskimo/Inuit population.4 In the Eskimos/Inuit population, salivary gland LELC is more common in women, predilects to the parotid gland, and has a more aggressive clinical course presents with higher clinical stage disease as compared to similar tumors occurring in other populations.4,8 The clinical presentation of LELC is usually that of a mass swelling with or without associated pain and/or facial nerve paralysis. In addition, there is a high frequency (10–40%) of concurrent cervical lymphadenopathy. In advanced tumors, fixation to skin and/or underlying structures may be present. Most LELCs develop de novo, but some may arise in association with lymphoepithelial sialadenitis (LESA).9 However, such “transformation” remains questionable, with the possibility that the presence of LESA in foci adjacent to LELC represents a reactive process and not a precursor lesion. There is no known association with other autoimmune disorders (e.g., Sjögren disease).
Etiology Salivary gland LELCs are linked to Epstein–Barr virus (EBV). Near 100% of LELCs in patients from endemic areas are
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associated with EBV.4,8,10–18 The presence of EBV in clonal episomal form suggests a role in tumor development. Elevated serologic titers of anti-EBV viral capsid antigen IgA and anti-EBV nuclear antigen IgG are seen in the majority of patients from endemic areas. In non-endemic areas, EBV is usually absent but may rarely be identified.4,19–22 The absence of EBV does not exclude the diagnosis.
Pathology Grossly, LELCs tend to be circumscribed but unencapsulated, lobulated, firm, tan–white masses measuring from 1 to 10 cm in greatest dimension. The histologic features include an infiltrative tumor characterized by the presence of lobules, sheets, nests, islands, trabeculae, or cords of neoplastic cells separated by or overrun by lymphoid stroma (Fig. 1). The neoplastic cells are polygonal to spindle-shaped with large round to oval, basophilic to vesicular-appearing nuclei, one or more prominent nucleoli, and abundant amphophilic to lightly eosinophilic cytoplasm (Fig. 1). The cells have indistinct cell borders and syncytial growth is usually evident. Moderate to marked nuclear pleomorphism, as well as increased mitotic activity and necrosis often are present. Focal squamous differentiation may be identified. In association with the carcinoma, a dense nonneoplastic lymphoplasmacytic cell infiltrate, with or without germinal centers, is commonly present. The lymphoplasmacytic cell infiltrate is usually identified between and around tumor nests or may overrun and obscure the carcinomatous component (Fig. 1). The presence of abundant histiocytes may be seen creating a “starry sky” appearance. Additional findings may include the presence of noncaseating granulomatous inflammation and an amyloid stroma. In some cases, especially those identified in Inuit population, a prominent basaloid morphology may be seen (Fig. 1).23 Such tumors have been referred to as basaloid LELCs and are also associated with EBV. In all cases, invasion is present, including into nonneoplastic salivary gland parenchyma, surrounding connective tissues, neurotropism, and/or angioinvasion.
Immunohistochemistry and molecular analysis The epithelial cells are reactive for cytokeratins (Fig. 2) and epithelial membrane antigen (EMA). Variable p63 reactivity is present from case to case and even within the same case, ranging from diffuse to focal reactivity (Fig. 2). c-Kit (CD117) reactivity may be present, but p16 is negative. In situ hybridization for Epstein–Barr encoded RNA (EBER) is consistently positive in cases from endemic regions irrespective of cell type (Fig. 2). In non-endemic populations, EBER is usually negative but may be positive. The lymphoid cells show reactivity for both B-cell (CD20) and T-cell (CD3) markers.
Treatment and prognosis The treatment for parotid gland LELC includes combined (multimodality) therapy including surgical resection, neck dissection, and radiation therapy.24 Up to 40% of patients may present with regional lymph node metastasis, thereby
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Fig. 1 – Lymphoepithelial-like carcinoma of the parotid gland. (A and B) Infiltrative but circumscribed cellular proliferation separated from the adjacent parotid gland parenchyma (left); the proliferation includes clusters of lighter-staining neoplastic foci in a background of dense lymphocytic cell infiltrate including germinal centers. Note the absence of an associated desmoplastic reaction to the infiltrative neoplasm. (C and D) Cohesive cluster of neoplastic cells characterized by cells with enlarged vesicular nuclei, prominent eosinophilic nucleoli, and indistinct borders creating a syncytial growth. These histologic features are similar to nasopharyngeal carcinoma nonkeratinizing undifferentiated type. Variant histologic features may include (E) fascicular growth with spindle-shaped neoplastic cells and (F) basaloid cell features.
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Fig. 2 – Lymphoepithelial-like carcinoma of the parotid gland. The lesional cells are (A) cytokeratin positive and (B) p63 positive (nuclear staining). In situ hybridization for Epstein–Barr encoded RNA (EBER) is positive irrespective of the cytomorphologic features, including (C) epithelioid cells, (D) spindle-shaped cells, and (E) basaloid cells. necessitating neck dissection.4 Local recurrence and distant metastasis may occur. The 3-year locoregional control (LRC), progression-free survival (PFS), and overall survival (OS) rates
were reported to be 94%, 92%, and 93%, respectively. The 5year survival rate for parotid gland LELC was reported to be as high as 86%.24
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Differential diagnosis Metastasis to the parotid gland from an EBV-associated nasopharyngeal carcinoma (NPC) should be considered and excluded prior to rendering a diagnosis of primary parotid gland LELC. It is not uncommon for NPCs to metastasize as occult primary carcinomas. LELCs share overlapping histologic and immunohistochemical findings to their nasopharyngeal counterparts. Differentiation is predicated on detailed clinical evaluation to exclude primary nasopharyngeal carcinoma. The absence of EBER, especially in a patient with parotid gland LELC, can be used in conjunction with clinical and radiologic findings to support a diagnosis of primary parotid LELC from NPC, as the latter is usually but not always EBER positive. Given the presence of the relatively recently described oropharyngeal human papillomavirus (HPV)-associated LELC25,26 (see below), it would be prudent to perform p16 staining in any carcinoma, including those of salivary glands, with histologic features of LELC that are negative for EBV to exclude a possible metastasis from a primary oropharyngeal LELC. Similar to the EBV-associated NPCs, oropharyngeal HPV-associated carcinomas may metastasize to cervical neck lymph nodes in the absence of a known primary carcinoma. In those cases of LELC that are EBER negative, the absence of p16 confirmed by the absence of high-risk HPV by molecular testing (e.g., in situ hybridization or polymerase chain reaction) allows for differentiation from a metastatic oropharyngeal HPV-associated carcinoma. The differential diagnosis also includes malignant lymphoma and malignant melanoma, but the presence of consistent and strong cytokeratin immunoreactivity and the absence of hematolymphoid markers (CD45, CD20, and others) and melanoma-related markers (S100 protein, HMB45, SOX10, melan A, tyrosinase, and MITF1) differentiate LELC from these other diagnostic considerations. The presence of overtly malignant cells differentiates LELC from lymphoepithelial sialadenitis. The histologic setting is
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similar to that of benign lymphoepithelial lesion except for the presence of a malignant epithelial component instead of a benign epithelial component. Transformation of a benign lymphoepithelial lesion to a malignant epithelial neoplasm (so-called malignant lymphoepithelial lesion) occurs much less frequently than transformation to malignant lymphoma. Although LELCs of salivary glands are rare tumors, these carcinomas most likely develop as de novo neoplasms unrelated to other conditions (e.g., lymphoepithelial sialadenitis). There is an increased incidence of malignant lymphoepithelial lesions among Eskimos in whom it is more common in men than in women and most frequently occurs in the 5th decade of life. Among Eskimos, the parotid gland is the most frequent site of occurrence; among Asians, the submandibular gland is most often involved. The histologic picture of carcinomatous component ranges from low to high grade. There is some evidence linking EBV with this neoplasm, but there is equal evidence showing an absence of EBV DNA in these neoplasms. Another entity to consider in the differential diagnosis from LELC is the rarely occurring primary salivary gland large cell undifferentiated carcinoma (LCUC), which is a high-grade malignant epithelial salivary gland tumor lacking evidence of glandular, squamous, or neuroendocrine differentiation and an inability to be classified in another (more specific) salivary gland carcinoma. In contrast to LELC, LCUC is a tumor of adults with patients usually in 7th–8th decades of life.27–31 There is no ethnic or racial predilection or association with EBV. The majority occur in the parotid gland, although submandibular gland, lacrimal gland, and minor salivary glands may rarely be primary sites of occurrence. The presentation is usually that of a rapidly enlarging mass, often with associated facial nerve paralysis and cervical lymphadenopathy; fixation to adjacent tissues is commonly present. The lesional cells in LCUC are large (usually measuring greater than 3 times the size of cells in small cell neuroendocrine carcinoma), polygonal with enlarged round to oval vesicular nuclei, one or more prominent nucleoli, abundant
Fig. 3 – Large cell undifferentiated carcinoma of the parotid gland. (A) Intraparotid infiltrative neoplasm appearing composed of markedly enlarged cells with pleomorphic round to oval nuclei with vesicular nuclear chromatin, prominent eosinophilic nucleoli, and indistinct eosinophilic cytoplasm. (B) The lesional cells are only reactive for cytokeratins in this example OSCAR. The cytomorphologic features coupled to absence of cellular differentiation and absence of EBER (not shown) allows for a diagnosis of large cell undifferentiated carcinoma and differentiation from other lesions, including lymphoepithelial-like carcinoma.
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amphophilic to eosinophilic cytoplasm, and rather distinct cell borders (Fig. 3). Marked nuclear pleomorphism is commonly seen but occasional cases may display nuclear uniformity. There is increased mitotic activity including atypical mitoses and tumor necrosis commonly identified. Multinucleated (osteoclast-like) giant cells may be identified. Invasion is readily apparent, including into nonneoplastic salivary gland parenchyma, surrounding connective tissues, perineural invasion, and lymphovascular invasion. A benign lymphoplasmacytic cell infiltrate may be present but does not approach the density and/ or extent seen in lymphoepithelial carcinoma. Immunohistochemical staining shows the lesional cells to be cytokeratin positive. Markers for EBV and HPV are invariably absent. Melanocytic, hematolymphoid, and mesenchymal markers are negative. Staining for neuroendocrine markers (e.g., synaptophysin) is negative and should be performed to exclude a possible diagnosis of the large cell type of neuroendocrine carcinoma. LCUCs are aggressively behaving tumors, with high rate of recurrence and metastases (regional and distant) with poor prognosis, including a 36% 2-year survival.25,32
Oropharyngeal lymphoepithelial-like carcinoma Clinical findings In 2010, Singhi et al.25 described a nonkeratinizing (lymphoepithelial-like) undifferentiated carcinoma of the oropharynx associated with human papillomavirus (HPV), thereby, representing a morphologic variant of HPV-related head and neck cancer.26 In terms of their anatomic localization, more than 90% occur in the tonsils and base of tongue and tend to occur in patients below 60 years of age and in nonsmokers. Symptoms may include oropharyngeal mass and/or neck mass and cervical lymph node involvement occurs in approximately 70% of cases at presentation. Oropharyngeal HPV-associated carcinomas including LELCs may metastasize as occult primary carcinomas.
Pathology The histomorphologic features of the oropharyngeal LELCs are similar to their nasopharyngeal counterparts, including the presence of lobules, sheets, nests, or cords of neoplastic cells separated by or overrun by lymphoid stroma (Fig. 4). The neoplastic cells include large round to oval nuclei with vesicular-appearing chromatin, one or more prominent nucleoli, and abundant amphophilic to lightly eosinophilic cytoplasm (Fig. 4). In association with the carcinoma, a dense nonneoplastic lymphoplasmacytic cell infiltrate is commonly present, identified in and around tumor nests, but may overrun and obscure the carcinomatous component.
Immunohistochemistry and molecular analysis The lesional cells are immunoreactive for cytokeratins and p16, the latter in greater than 70% of lesional cells, including nuclear and cytoplasmic staining (Fig. 4); EBER staining is negative. Molecular analysis (e.g., in situ hybridization and polymerase chain reaction) shows the presence of transcriptionally active virus in the majority of cases.
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Treatment and prognosis Oropharyngeal LELCs are radiosensitive cancers and as a result the disease-specific survival is good, comparable to those associated with HPV-related oropharyngeal squamous cell carcinoma and better than that of HPV-negative carcinomas.27
Differential diagnosis Primary nasopharyngeal EBV-associated carcinoma (nonkeratinizing undifferentiated type) and primary oropharyngeal HPV-associated LELC may present as lymph node metastases in the absence of a known primary cancer. Differentiation of these 2 tumor types and therefore determination of the primary site of origin would be based on the presence or absence of EBV and HPV. Given the identical histologic features shared by primary nasopharyngeal EBV-associated carcinoma (nonkeratinizing undifferentiated type) and primary oropharyngeal HPV-associated LELC, when confronted with cervical lymph node metastasis without a known primary cancer in which the tumor is an undifferentiated carcinoma (cytokeratin positive), the work up should include evaluation for both EBV and HPV. The differential diagnosis also includes malignant lymphoma and malignant melanoma, but the presence of consistent and strong cytokeratin immunoreactivity and the absence of hematolymphoid markers (CD45, CD20, and others) and melanoma-related markers (S100 protein, HMB45, SOX10, melan A, tyrosinase, and MITF1) differentiate LELC from these other diagnostic considerations.
Sinonasal tract lymphoepithelial-like carcinoma Clinical findings Rare examples of sinonasal tract carcinomas morphologically similar to their histologic counterparts in the nasopharynx have been described.2,33,34 The sinonasal LELCs primarily affect men in the 5th–7th decades of life. Sinonasal LELCs more commonly occur in the nasal cavity than the paranasal sinuses. The clinical presentation includes nasal obstruction, epistaxis and, in the presence of invasive growth, proptosis, and cranial nerve palsies.
Etiology Similar to its nasopharyngeal counterpart, there is a strong association with EBV,2,33,34 but not all cases are EBV positive.2
Pathology The histologic findings include the presence of a submucosal infiltrative neoplastic proliferation characterized by varying growth patterns, including trabeculae, cords, islands, lobules, and sheets, often without a desmoplastic stromal reaction (Fig. 5). The neoplastic cells include large round to oval nuclei with vesicular-appearing chromatin, one or more prominent nucleoli, and abundant amphophilic to lightly eosinophilic cytoplasm (Fig. 5). Indistinct cell borders result in syncytial
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Fig. 4 – Lymphoepithelial-like carcinoma of the oropharynx. (A) Submucosal clusters of lesional cells with associated dense lymphoplasmacytic cell infiltrate and absence of stromal desmoplastic reaction. (B) Histomorphologic features are similar to those of EBV-associated nasopharyngeal carcinoma nonkeratinizing undifferentiated type, including cells with enlarged pleomorphic and vesicular nuclei and prominent nucleoli. Lesional cells are (C) cytokeratin positive and (D) p16 positive. EBER staining was negative (not shown). Subsequent evaluation by polymerase chain reaction confirmed the presence of high-risk human papillomavirus (not shown). This carcinoma can metastasize to cervical neck lymph nodes as an occult primary carcinoma. In such a scenario, purely based on the light microscopic features, a primary (EBV-associated) nasopharyngeal carcinoma would be the most likely consideration. EBER staining would be negative and unless consideration was given for a possible oropharyngeal origin, p16 staining which would be diagnostic might not be ordered. appearance. Nuclear pleomorphism is present, but generally there is an absence of increased mitotic activity. Necrosis is uncommon but may be present including central comedotype. Keratinization is usually not evident. In association with the carcinoma, a dense nonneoplastic lymphoplasmacytic cell infiltrate is commonly present but is typically less prominent as compared to nasopharyngeal carcinoma.
Immunohistochemistry and molecular analysis The lesional cells are cytokeratin positive and are strongly EBER positive (Fig. 5). There is an absence of immunoreactivity for hematolymphoid markers, melanoma-related markers, and neuroendocrine/neuroectodermal markers. P16 staining is absent.
Treatment and prognosis Treatment of sinonasal LELCs includes surgery combined with radiotherapy or chemoradiation.2 The prognosis is favorable owing to a good response to local radiotherapy. Regional cervical lymph node metastasis may be seen at presentation. The favorable prognosis is not altered even in the presence of nodal metastasis. The mortality rate of adequately treated LELC patients is low.2
Differential diagnosis In the sinonasal tract, a more common malignant undifferentiated neoplasm that is cytokeratin positive is the sinonasal
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Fig. 5 – Sinonasal lymphoepithelial-like carcinoma. (A) Polypoid invasive lesion with broad interconnecting cords of tumor similar to the growth pattern seen in sinonasal nonkeratinizing carcinoma. (B) The lesional cells are epithelioid and spindleshaped. (C) Both cell types (epithelioid shown here) are comprised of enlarged vesicular nuclei and prominent eosinophilic nuclei. Increased mitotic activity is present. (D) A focus of central comedotype necrosis is present. Lesional cells are immunoreactive for (E) cytokeratin (AE1/AE3) and (F) in situ hybridization for Epstein–Barr encoded RNA (EBER).
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undifferentiated carcinoma (SNUC), a highly aggressive and clinicopathologically distinctive carcinoma of uncertain histogenesis that typically presents with locally extensive disease and by definition lacks evidence of any type of cellular differentiation, including squamous, glandular, and neuroendocrine/neuroectodermal (e.g., neurofibrillary material and neural rosettes).35 SNUCs are more common in men than in women and tend occur over a wide age range, including 3rd–9th decades of life, with a median at presentation in the 6th decade. Typically, patients present with multiple symptoms that include nasal obstruction, epistaxis, proptosis, visual disturbances (e.g., diplopia), facial pain, and symptoms of cranial nerve involvement. A rather characteristic clinical phenomenon is the development of symptoms over relatively short duration (weeks to months). Further, at presentation, SNUCs often are extensively infiltrative, involving multiple sites, including the nasal cavity, one or more paranasal sinuses, orbit, skull base, and the brain. Most patients have unilateral disease but bilateral disease may occur. SNUC is a tumor of uncertain histogenesis. Although not definitively proven, given the presence in some examples of intraepithelial dysplasia/carcinoma in situ, it seems reasonable to consider that SNUCs arise from the Schneiderian epithelium and, therefore, are of ectodermal derivation. There are no known etiologic agents. SNUCs are typically negative for EBV in patients from Western populations,36,37 although EBV RNA has been identified in patients from Asian populations.36 Human papillomavirus (HPV) by p16 immunohistochemistry has been identified in a limited number of SNUCs,38,39 rarely with identification of transcriptionally active virus.39 It remains uncertain whether there is a relationship between HPV and SNUCs. SNUCs are characterized by hypercellular proliferation with varied growth, including trabecular, sheet-like, ribbons, solid, lobular, and organoid patterns. The cellular infiltrate consists of polygonal cells composed of medium- to large-sized, round to oval, hyperchromatic to vesicular nuclei, inconspicuous to prominent nucleoli, and a varying amount of eosinophilicappearing cytoplasm with poorly defined cell membranes, although distinct cell borders may be present; occasionally, cells with clear cytoplasm can be identified. There is increased mitotic activity, including atypical mitoses, and tumor necrosis (confluent areas and individual cells) is often present. SNUCs are extensively infiltrative, effacing the normal architecture of the sinonasal submucosa, and may include the presence of neurotropism, angioinvasion, and invasion of soft tissues (e.g., bone and other). Further, the brain may also be involved, representing evidence of invasion into the central nervous system. SNUCs are consistently immunoreactive with epithelial markers, including pankeratins and simple keratins (i.e., CK 7, CK8, and CK19); reactivity for pankeratins is often intense and diffuse. Variable reactivity can be identified for p63, including some cases with scattered focal positive staining, some cases completely negative, and less common diffuse p63 positivity. Focal reactivity for synaptophysin, chromogranin, CD56, and CD57 (Leu-7) may be seen. Mesenchymal, hematolymphoid, and melanoma-related markers are absent. The majority of cases are negative for EBV, but as previously indicated, there are reports of EBV identified in
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patients with SNUC. More likely, such EBV-positive SNUCs are sinonasal lymphoepithelial-like carcinomas,37 given differences in the response to treatment and in prognosis between SNUCs and sinonasal LELCs. Also as previously indicated, HPV (by p16 immunohistochemistry and molecular analysis) has been identified in a limited number of SNUCs, but it remains uncertain whether there is a relationship between HPV and SNUCs. Further, HPV-positive SNUCs may benefit from improved survival, but this finding requires further substantiation. For SNUCs, multimodality therapy is considered the best treatment approach to provide the best chance for survival and includes radical surgery and postoperative chemoradiotherapy. Generally, SNUCs are considered highly aggressive neoplasms with poor survival. Local recurrence is common and is the major cause of morbidity and mortality. Metastatic spread occurs to the bone, brain, liver, and cervical lymph nodes. The causes of death primarily relate to distant metastases. Another sinonasal tract malignant neoplasm that may be histologically undifferentiated and associated with EBV is the extranodal NK/T cell lymphoma and nasal type. However, the light microscopic features and immunoreactivity for CD3 (cytoplasmic), CD56, cytotoxic granules markers (e.g., granzyme B, cytotoxic granule-associated TIA-1, and perforin), and absence of cytokeratin allows for differentiation from sinonasal LELC.
Laryngeal lymphoepithelial-like carcinoma Clinical findings Rare examples of LELC have been reported in the larynx.40–45 These tumors are more common in men than in women and most frequently occur in older ages (7th decade or later of life). In the larynx, LELCs are more common in Caucasian populations than in Asian populations. Symptoms include hoarseness and a neck mass and less often, sore throat, dysphagia, hemoptysis, and otalgia. There is a tendency for these tumors to occur in the supraglottic larynx. Risk factors for the development of this carcinoma may include excessive use of tobacco and alcohol.43 Laryngeal LELCs are rarely associated with EBV.41,44,46
Pathology The histology of laryngeal LELCs is similar to its more common nasopharyngeal counterpart, including aggregates or syncytia of neoplastic cells characterized by enlarged vesicular nuclei and prominent nucleoli. Intraepithelial dysplasia and/or foci of squamous cell differentiation, including abrupt keratinization of conventional foci of squamous cell carcinoma, can be seen. A prominent benign lymphocytic cell infiltrate is present; a variable amount of plasma cell may be present.
Immunohistochemistry and molecular analysis The lesional cells are immunoreactive for cytokeratins. EBER is typically negative. There is an absence of immunoreactivity for neuroendocrine markers and melanoma-related markers.
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Treatment and prognosis Treatment varies and has including limited to radical surgery with adjuvant therapy (radiation and chemotherapy). Cervical nodal metastases occur in nearly 75% of patients; distant metastases, including to the lung, liver, bone, and skin, occur in approximately 25% of patients.41 Nearly one-third of patients reported death due to disease at a 21-month median follow-up.41
Differential diagnosis In the larynx, particularly the supraglottic larynx, the differential diagnosis includes laryngeal large cell neuroendocrine carcinoma (LCNEC), a relatively recently identified distinct subtype of poorly differentiated neuroendocrine carcinoma.47,48 The criteria for diagnosis of LCNEC include (1) the presence of features of neuroendocrine differentiation,
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including organoid nesting, trabecular growth, rosettes, and peripheral palisading; (2) the presence of enlarged tumor cells with vesicular chromatin, small to prominent nucleoli, and moderate to abundant cytoplasm; (3) increased mitotic activity [greater than 10 mitoses per 10 high-power fields (2 mm2)]; and (4) confirmation of neuroendocrine differentiation using immunohistochemical staining for chromogranin, synaptophysin, neuron-specific enolase, and/or neural cell adhesion molecule.48 The presence of neuroendocrine differentiation by light microscopic and immunohistochemical staining provide the means for differentiating LELC from LCNEC. Differentiation of LCNEC from LELC is important as the treatment and prognosis markedly varies. The treatment for LCNEC includes chemoradiotherapy. Commonly, patients with LCNEC present with advanced-stage clinical disease (stages III and IV), including locoregional metastases to cervical lymph nodes and distant visceral metastases (e.g., liver and other).48 The 5-year disease-specific survival (DSS) rate is reported to be 15–21%.48
Fig. 6 – Primary middle ear lymphoepithelial-like carcinoma. (A) Polypoid lesion that originated from the middle ear with dense submucosal lymphoid proliferation obscuring an infiltrative neoplasm (arrows). (B) At higher magnification epithelioid and spindle-shaped cells with enlarged vesicular nuclei and prominent eosinophilic nuclei are identified. (C) Lesional cells are immunoreactive for cytokeratin (AE1/AE3). (D) In situ hybridization for Epstein–Barr encoded RNA (EBER).
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Primary LELC of the middle ear and temporal bone In addition to the aforementioned sites of occurrence, LELCs may rarely originate in other head and neck sites. A rare site of occurrence includes the middle ear mucosa.49–52 Primary LELC arising in the middle ear is rare, with only 6 cases reported in the literature.49–52 All of these cases were reported in adult patients and all (100%) of these reported cases were associated with EBV, regardless of the age, gender, or nationality of the affected individual. Of interest is the fact that of the 6 reported cases, 4 were from the Guangdong province of China and 1 was a Filipino; the nationality of the remaining patient was not indicated. All of the patients had a history of long-standing otitis media and symptoms included hearing loss, aural fullness, or pressure sensation with or without discharge, pain, and cranial nerve palsies. Otoscopic examination findings were similar in all the cases, including the presence of polypoid granulation tissue-like mass in the middle ear cavity extending to external auditory canal. Clinical and radiologic evaluation showed the tumors limited to the middle ear/temporal bone albeit with extension to the external canal but no evidence of nasopharyngeal involvement and/or tracking of tumor from the nasopharynx to the middle ear via the eustacian tube. The histopathological findings may include the presence of a polypoid-appearing lesion with clusters or syncytia of epithelial cells with associated lymphoplasmacyticappearing infiltrate overrunning and/or obscuring the lesional cells (Fig. 6). The lesional cells are round to oval to spindle-shaped with vesicular-appearing nuclei and enlarged nucleoli (Fig. 6). Nuclear pleomorphism is present, but generally there is an absence of increased mitotic activity and necrosis. In spite of the infiltrative nature of the neoplasm, there may be an absence of an associated desmoplastic stromal reaction. Intact surface flattened to cuboidal (middle ear) epithelium may be present.
Immunohistochemistry and molecular analysis The lesional cells are immunoreactive for cytokeratins and EBER (Fig. 6).
Treatment and prognosis The optimal treatment modality remains unclear. From the limited available data, surgery and postoperative radiotherapy are considered appropriate therapeutic modalities.
Differential diagnosis The absence of an associated desmoplastic stromal reaction and presence of obscuring lymphoplasmacytic infiltrate may result in overlooking the lesional cells and a misdiagnosis. Given the presence of a polypoid lesion with associated dense lymphoplasmacytic cell infiltrate, consideration may be given to a diagnosis of a middle ear otic or aural polyp, a lesion predominantly occurring in children. Alternatively, a diagnosis of nonspecific chronic otitis media may be rendered, especially given the clinical presentation of long-standing otitis media. Close attention to the histologic findings,
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including clusters of lesional cells with enlarge vesicular nuclei and prominent nucleoli should allow for consideration of the rare diagnosis of middle ear LELC.
Conclusion Lymphoepithelial-like carcinomas of the head and neck are histologically similar to nasopharyngeal carcinoma nonkeratinizing undifferentiated type but by definition arise in mucosal sites other than the nasopharynx. LELCs are an uncommon but well-recognized entity. Similar to their nasopharyngeal counterparts, the majority of lymphoepitheliallike carcinomas in other head and neck sites are associated with Epstein–Barr virus. However, for carcinomas of the head and neck that exhibit lymphoepithelial features, an EBVdriven process by morphology alone cannot be assumed. HPV testing has disclosed a morphologic variant of HPVassociated carcinoma in the oropharynx that is histologically indistinguishable from the EBV-related carcinoma. Treatment of LELCs largely consists of surgery, combined with radiotherapy or chemoradiation. Although local spread or nodal metastases are fairly common at the time of diagnosis, the mortality rate of adequately treated LELC patients appears to be low.
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