Mediastinum
Thymic carcinoma
Lymphoepithelial carcinoma
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Editor-in-Chief: Debra L. Zynger, M.D.
Last author update: 16 January 2023
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PubMed Search: Lymphoepithelial carcinoma
Table of Contents
Definition / general | Essential features | Terminology | ICD coding | Epidemiology | Sites | Etiology | Clinical features | Diagnosis | Radiology description | Prognostic factors | Case reports | Treatment | Microscopic (histologic) description | Microscopic (histologic) images | Positive stains | Negative stains | Electron microscopy description | Electron microscopy images | Molecular / cytogenetics description | Sample pathology report | Differential diagnosis | Board review style question #1 | Board review style answer #1 | Board review style question #2 | Board review style answer #2Cite this page: Suster D, Mackinnon AC. Lymphoepithelial carcinoma. PathologyOutlines.com website. https://www.pathologyoutlines.com/topic/mediastinumLEL.html. Accessed December 26th, 2024.
Definition / general
- Also known as poorly differentiated, nonkeratinizing, squamous cell thymic carcinoma or lymphoepithelioma-like thymic carcinoma
- Originates from thymic epithelial cells and shows histologic and immunophenotypic evidence of squamous differentiation
- WHO classification: lymphoepithelial carcinoma of the thymus
Essential features
- Defined as a primary thymic epithelial neoplasm displaying overt cytologic evidence of malignancy with loss of organotypical features of thymic differentiation
- Diagnosis of exclusion
- Invasive growth pattern of nests and cords of tumor cells, which grow in sheets with a syncytial growth pattern and have vesicular nuclei with prominent nucleoli
- Often have prominent associated lymphoid infiltrate within fibrous stroma
- Some (~50%) cases are associated with Epstein-Barr virus (EBV) (Cancers (Basel) 2021;13:4794)
Terminology
- Thymic carcinoma
- Lymphoepithelial carcinoma
- Poorly differentiated, nonkeratinizing, squamous cell thymic carcinoma
- Lymphoepithelioma-like carcinoma
ICD coding
- ICD-10: C37 - thymic carcinoma (malignant)
Epidemiology
- M > F (~3:1)
- Average age of 60 years (range: 20 - 85 years)
Sites
- Predominantly located in the anterior mediastinum (Am J Surg Pathol 2018;42:1224)
Etiology
- Remains unknown
- Epstein-Barr virus has been reported in some cases, predominantly in younger patients; however, EBV tends to be negative in older patients
- In the largest study, only 4% of cases were positive for EBER by in situ hybridization (Am J Surg Pathol 2018;42:1224)
- Other studies have reported a rate of EBV positivity as high as 50% (Cancers (Basel) 2021;13:4794, Infect Agent Cancer 2019;14:32)
- No pathognomonic molecular alterations have been identified
Clinical features
- Presents with anterior mediastinal masses, often found incidentally
- When symptomatic, clinical symptoms include chest pain, shortness of breath and weight loss (Am J Surg Pathol 2018;42:1224)
Diagnosis
- Diagnosis of exclusion
- Requires the presence of a poorly differentiated carcinoma primary to the thymus with an invasive growth pattern of nests and cords of tumor cells with syncytial growth and vesicular nuclei with prominent nucleoli
Radiology description
- Typically appears as well demarcated anterior mediastinal masses
- Positron emission tomography (PET) usually shows mild to moderate PET avidity
Prognostic factors
- Staging at time of diagnosis is the most important prognostic factor
- Staging performed using the AJCC 8th edition staging system for thymic carcinoma (J Thorac Oncol 2022;17:838)
- Modified Masaoka staging system is optional (Thorac Cardiovasc Surg 2014;62:153)
- Completeness of resection is an important prognostic factor as well
Case reports
- 14 year old boy with metastatic carcinoma (Oncol Lett 2014;8:2183)
- 26 year old man who presented initially with back pain (BMJ Case Rep 2017;2017:bcr2017221478)
- 42 year old man with multiple lung, bone and brain metastases (Acta Neurol Taiwan 2010;19:41)
- 52 year old man with complaints of left anterior chest pain (Kyobu Geka 2003;56:509)
- 52 year old man and 64 year old woman underwent complete surgical resection for thymic lymphoepithelioma-like carcinoma (Am J Transl Res 2021;13:1896)
- 60 year old man with right sided neck mass found to be an intrathyroidal lymphoepithelioma-like thymic carcinoma (APMIS 1996;104:419)
- 65 year old woman with chest pain and 81 year old woman with abnormal shadow on chest Xray (Surg Case Rep 2019;5:158)
Treatment
- Surgical resection is still the predominant treatment
- Radiotherapy may increase local regional relapse free survival with mild toxicities in advanced stage patients (Ann Thorac Surg 2017;104:1718)
- In the largest study, 14 of 20 patients had no evidence of disease between 1.5 and 16 years after diagnosis (median survival: 4 years; mean survival: 5.5 years) (Oncol Lett 2014;8:2183)
Microscopic (histologic) description
- Invasive growth pattern of cords, nests and trabeculae separated by fibrous stroma with variable prominent mature lymphoid infiltrates
- 2 patterns of growth described (Am J Surg Pathol 2018;42:1224):
- Lymphoepithelioma-like pattern: irregular cords and islands of tumor cells separated by connective tissue stroma containing dense lymphoplasmacytic infiltrates
- Desmoplastic pattern: irregular cords and nests of tumor cells separated by fibrous stroma with minimal inflammatory infiltrates
- Can have both patterns
- Can show focal areas of abrupt keratinization
- Prominent areas of comedonecrosis
- Uniform, poorly differentiated tumor cell population with round to oval nuclei, vesicular chromatin, prominent round eosinophilic nucleoli and an indistinct rim of eosinophilic cytoplasm
- Syncytial growth pattern of tumor cells with rare pleomorphic and multinucleated cells
Microscopic (histologic) images
Contributed by David Suster, M.D.
Sheets of large round to oval tumor cells
Anastomosing cords, islands, comedonecrosis
Comedonecrosis
Lymphoepithelioma-like pattern
Desmoplastic pattern
Focal abrupt keratinization
p63
Positive stains
- 100%: keratin AE1 / AE3, CK5/6, CK18, MOC31, p40, p63 and p16 (Am J Surg Pathol 2018;42:1224)
- CD5 (80%) (Appl Immunohistochem Mol Morphol 2014;22:372)
- CD117 (84%) (Appl Immunohistochem Mol Morphol 2014;22:372)
- Variable positivity for p53, CK7, CK19 and synaptophysin (Am J Surg Pathol 2018;42:1224)
- Lymphoid cells: mixture CD3 and CD20 (Am J Surg Pathol 2018;42:1224)
Negative stains
- NUTM1, calcitonin, calretinin and TTF1 (Am J Surg Pathol 2018;42:1224)
- Lymphoid cells: TdT (Am J Surg Pathol 2018;42:1224)
Electron microscopy description
- Cohesive population of large cells with round to oval nuclei containing a single nucleolus and scattered heterochromatin (Am J Surg Pathol 2018;42:1224)
- Abundant junctional complexes, with dense plaques and well formed desmosomes containing attached short tonofilaments (Am J Surg Pathol 2018;42:1224)
Electron microscopy images
Contributed by David Suster, M.D.
Large, round tumor cell
2 desmosomal attachments
Molecular / cytogenetics description
- EBER rarely identified (Am J Surg Pathol 2018;42:1224)
- Molecular studies reveal a heterogeneous group of variants with low numbers of mutations, similar to other molecular studies done on thymic carcinoma
- 5 patients had somatic variants in 6 genes known to play a significant role in tumor development and growth, including IDH1, CDKN2A, FGFR3 and others (Am J Surg Pathol 2018;42:1224)
Sample pathology report
- Thymus, resection:
- Poorly differentiated thymic squamous cell carcinoma, predominantly nonkeratinizing (lymphoepithelial carcinoma) (see synoptic report and comment)
- Comment: The tumor cells are positive for p40, CD117, CD5 and PDL1.
Differential diagnosis
- Metastatic poorly differentiated lung carcinoma:
- Atypical thymoma:
- Basaloid thymic carcinoma:
- Less comedonecrosis and basal palisading of the nuclei
- Lack distinct nucleoli and cleared out vesicular cytoplasm
- NUT carcinoma:
- NUT1+
- NUT::BRD translocations can be identified by FISH
- Metastatic lymphoepithelial carcinoma:
- Lymphoepithelial carcinoma may arise in extramediastinal locations as a primary tumor
- Outside the mediastinum these tumors tend to be strongly correlated with EBV positivity
- Strict clinical correlation and detailed history required to rule out metastasis
Board review style question #1
A 62 year old patient presented with a 9 cm anterior mediastinal mass (see image above). What would help differentiate this lesion from a metastasis from a head and neck lymphoepithelioma-like thymic carcinoma?
- Detailed clinical history
- Immunohistochemistry for p63 and cytokeratins
- In situ hybridization for EBER
- In situ hybridization for HPV
- Next generation sequencing
Board review style answer #1
A. Detailed clinical history. Immunohistochemistry and in situ hybridization in general are unhelpful in distinguishing lymphoepithelial carcinomas from different sites. Although a much lower percentage of lymphoepithelial carcinomas test positive for EBV compared to other primary sites, a significant proportion are still reported to express EBV. HPV ISH would not be helpful as it would be expected to be negative. The most useful way to separate these tumors is through a detailed clinical history, including thoracic and head and neck radiologic studies.
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Reference: Lymphoepithelial carcinoma
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Reference: Lymphoepithelial carcinoma
Board review style question #2
Which immunohistochemical stains would be most helpful in distinguishing a primary squamous cell thymic carcinoma from metastatic lesions from other primary sites?
- CD5 and CD117
- Cytokeratins
- p16
- p63
Board review style answer #2
A. CD5 and CD117 would be the most helpful in establishing thymic origin in this scenario. While primary lymphoepithelioma-like thymic carcinoma will express keratins, p16 and p63, so would poorly differentiated squamous cell carcinomas elsewhere in the body; however, few lesions outside the body would have CD5 and CD117 positivity.
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Reference: Lymphoepithelial carcinoma
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