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A 65-Year-Old Man With Persistent Cough and Large Nodular OpacityPersistent Cough and Large Nodular Opacity FREE TO VIEW

Brandon S. Grimes, MD; Jeffrey Albores, MD; Igor Barjaktarevic, MD
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From the Department of Pulmonary and Critical Care Medicine, University of California Los Angeles Medical Center, Los Angeles, CA.

CORRESPONDENCE TO: Brandon S. Grimes, MD, UCLA Medical Center, Pulmonary and Critical Care Medicine, 37-131 CHS 10833 Le Conte Ave, Los Angeles, CA 90095; e-mail: BGrimes@mednet.ucla.edu


Reproduction of this article is prohibited without written permission from the American College of Chest Physicians. See online for more details.


Chest. 2015;147(1):e13-e17. doi:10.1378/chest.14-1172
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Published online

A 65-year-old Asian man with a history of chronic hepatitis B infection presented to our pulmonary clinic for second opinion of his chronic, persistent, nonproductive cough. He was evaluated 10 months earlier with chest CT scan, which revealed a large lingular nodular opacity that was diagnosed as nodular cryptogenic organizing pneumonia by CT scan-guided percutaneous lung biopsy. Systemic corticosteroids were initiated and continued over the next 10 months. The dry cough persisted, and he developed intermittent left-sided pleuritic chest pain. He denied fevers, night sweats, hemoptysis, weight loss, or dyspnea. He was a lifelong nonsmoker and moved to the United States from China during childhood.

Figures in this Article

Vital signs were BP 141/72 mm Hg, pulse 97 beats/min, respiration 16 breaths/min, and oxygen saturation of 96% on ambient air. He was a thin man who persistently coughed throughout the examination. Auscultation of his chest revealed diminished breath sounds in the left middle and lower lung zones. No rales, rhonchi, or wheeze was heard. The rest of the physical examination was unremarkable.

CBC count and metabolic panel were normal. Chest CT scan showed an 11 × 7 cm mass-like consolidation within the lingula with complete obstruction of the lingular segmental bronchus and extension across the fissure into the left lower lobe (Fig 1). Bulky mediastinal lymphadenopathy was also present. Compared with the initial chest CT scan, the consolidation was unchanged in size. The lesion was fluorodeoxyglucose avid on PET scan (Fig 2). Review of his prior surgical lung biopsy pathology slides suggested a possible lymphoproliferative process in addition to previously noted features of organizing pneumonia. CT scan-guided core needle biopsy was performed to obtain a definitive diagnosis. Microscopic examination of the tissue demonstrated atypical epithelial cells in clusters with a dense background of lymphohistiocytic infiltration. Immunohistochemical staining was notably positive for cytokeratin. In situ hybridization for Epstein-Barr virus (EBV)-encoded small nuclear RNA was strongly positive (Fig 3).

Figure Jump LinkFigure 1 –  Chest CT scan lung window showing a large, well-defined mass-like consolidation within the lingula. There was mass extension across the fissure into the left lower lobe with bulky mediastinal lymphadenopathy.Grahic Jump Location
Figure Jump LinkFigure 2 –  A, Chest CT scan mediastinal window showing the large, well-defined mass-like consolidation within the lingula. B, PET-CT scan demonstrating the lesion to be fluorodeoxyglucose avid.Grahic Jump Location
Figure Jump LinkFigure 3 –  Core needle biopsy of the left lower lobe nodular opacity. A, Tumor composed of nests and sheets of epithelial cells with a very prominent lymphoplasmacytic infiltrate (hematoxylin and eosin, original magnification × 100). B, Epithelial cell nests highlighted by pan-keratin stain (Keratin AE1/3 immunohistochemistry, original magnification × 200). C, Epstein-Barr virus (EBV)-encoded small nuclear RNA stain showing EBV involvement (in situ hybridization, original magnification × 100).Grahic Jump Location
What is the diagnosis?
Diagnosis: Pulmonary lymphoepithelioma-like carcinoma

Primary pulmonary lymphoepithelioma-like carcinoma (LELC) is an extremely rare form of non-small cell lung cancer, most recently classified by the World Health Organization as a subtype of large cell lung cancer. There are fewer than 200 cases reported in the literature since the entity was first described in 1987. The majority of cases have been reported in Southeast Asian populations, with only a handful in Western populations. The disease occurs commonly in men and is often diagnosed in the fourth through sixth decades of life. There is no known association between pulmonary LELC and tobacco use.

Primary pulmonary LELC is histologically indistinguishable from LELC originating in the nasopharynx, known as undifferentiated nasopharyngeal carcinoma, which is a common malignancy. LELC has also been reported in many other sites, including the stomach, hepatobiliary system, thymus, bladder, and uterus.

A strong association exists between EBV and pulmonary LELC. Approximately 75% of all primary pulmonary LELC tumors are EBV-positive. Interestingly, this association appears to depend on racial and geographic factors. Nearly all patients of Asian descent have EBV-positive tumors, whereas nearly all patients of Western origin are EBV-negative. Although a monoclonal EBV genomic pattern has been shown within some EBV-positive LELC tumors, no definite causative role has established.

Clinical presentation is variable, and patients are often asymptomatic at the time of diagnosis. If symptomatic, a nonproductive cough and chest discomfort are commonly described. On imaging, the tumors are usually large at the time of diagnosis, located centrally, and associated with smooth borders and vascular encasement. PET scanning usually demonstrates increased fluorodeoxyglucose uptake within the tumor. The most important differential diagnoses to exclude are non-Hodgkin’s lymphoma or metastatic LELC of nasopharyngeal origin. For this reason, an endoscopic or radiologic examination of the nasopharynx should always be performed. Nodular cryptogenic organizing pneumonia can have a similar appearance on imaging, but histopathology will differentiate this from LELC. Histopathologic examination with immunohistochemical staining is necessary to confirm the diagnosis of LELC. Microscopic examination of the tumor classically reveals nests of epithelial tumor cells with prominent nucleoli in syncytial arrangements, which are surrounded by a marked lymphoplasmacytic infiltrate. Tumor cells demonstrate immunoreactivity for cytokeratin but not for leukocyte common antigen. In situ hybridization for EBV-encoded small nuclear RNA within tumor cells is positive in the majority of cases.

Staging of pulmonary LELC is identical to other non-small cell lung cancers and uses the TNM staging system. The majority of reported cases are diagnosed at early stages (stages I or II), where complete surgical resection is the mainstay of treatment. In advanced or metastatic disease (stage IIIA and above), there is no standardized treatment protocol, given the rarity of this occurrence. Most of these patients are treated with combination of radiotherapy and/or chemotherapy based on small case series. Multiple chemotherapy protocols have been reported to be effective, including combined 5-FU and cisplatin, single-agent capecitabine, and Taxol-based or docetaxel-based regimens.

Compared with other non-small cell lung cancers, primary pulmonary LELC carries a significantly better prognosis. Overall survival rates for pulmonary LELC have been reported as 80% and 54% at 2 and 5 years, respectively. Limited data suggest that this difference is more pronounced in patients with advanced disease. Disease recurrence is rare following successful complete resection in patients with early-stage disease. Good prognostic indicators include early-stage disease, absence of lymph node metastasis, normal serum lactate dehydrogenase, and normal serum albumin.

Clinical Course

The diagnosis of primary pulmonary LELC was made based on histopathologic and immunohistochemical findings. There was no evidence of nasopharyngeal lesion on examination or imaging to suggest a nasopharyngeal origin of his LELC. Unfortunately, before treatment could be initiated, the patient developed fulminant liver failure secondary to reactivation of his chronic hepatitis B viral infection. He had a rapid clinical deterioration thereafter and died within weeks of the diagnosis.

  • 1. Primary pulmonary LELC is an extremely rare form of non-small cell lung cancer that occurs primarily in patients of Southeast Asian descent.

  • 2. A strong association exists between LELC and EBV, which is dependent on geographic and racial factors.

  • 3. It is important to evaluate the nasopharynx for evidence of a primary tumor with endoscopy or MRI.

  • 4. Primary pulmonary LELC carries a better prognosis than other types of non-small cell lung cancer, even in the presence of advanced or metastatic disease.

Financial/nonfinancial disclosures: The authors have reported to CHEST that no potential conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article.

Other contributions:CHEST worked with the authors to ensure that the Journal policies on patient consent to report information were met. We thank Dean Wallace, MD, Department of Pathology, University of California Los Angeles, for assistance with the pathology illustrations.

Castro CY, Ostrowski ML, Barrios R, et al. Relationship between Epstein-Barr virus and lymphoepithelioma-like carcinoma of the lung: a clinicopathologic study of 6 cases and review of the literature. Hum Pathol. 2001;32(8):863-872. [CrossRef] [PubMed]
 
Han AJ, Xiong M, Gu YY, Lin SX, Xiong M. Lymphoepithelioma-like carcinoma of the lung with a better prognosis. A clinicopathologic study of 32 cases. Am J Clin Pathol. 2001;115(6):841-850. [CrossRef] [PubMed]
 
Hayashi T, Haba R, Tanizawa J, et al. Cytopathologic features and differential diagnostic considerations of primary lymphoepithelioma-like carcinoma of the lung. Diagn Cytopathol. 2012;40(9):820-825. [CrossRef] [PubMed]
 
Liang Y, Wang L, Zhu Y, et al. Primary pulmonary lymphoepithelioma-like carcinoma: fifty-two patients with long-term follow-up. Cancer. 2012;118(19):4748-4758. [CrossRef] [PubMed]
 
Huang Y, Hsueh C, Ho SY, Liao CY. Lymphoepithelioma-like carcinoma of the lung: an unusual case and literature review. Case Rep Pulmonol. 2013;2013:143405. [PubMed]
 

Figures

Figure Jump LinkFigure 1 –  Chest CT scan lung window showing a large, well-defined mass-like consolidation within the lingula. There was mass extension across the fissure into the left lower lobe with bulky mediastinal lymphadenopathy.Grahic Jump Location
Figure Jump LinkFigure 2 –  A, Chest CT scan mediastinal window showing the large, well-defined mass-like consolidation within the lingula. B, PET-CT scan demonstrating the lesion to be fluorodeoxyglucose avid.Grahic Jump Location
Figure Jump LinkFigure 3 –  Core needle biopsy of the left lower lobe nodular opacity. A, Tumor composed of nests and sheets of epithelial cells with a very prominent lymphoplasmacytic infiltrate (hematoxylin and eosin, original magnification × 100). B, Epithelial cell nests highlighted by pan-keratin stain (Keratin AE1/3 immunohistochemistry, original magnification × 200). C, Epstein-Barr virus (EBV)-encoded small nuclear RNA stain showing EBV involvement (in situ hybridization, original magnification × 100).Grahic Jump Location

Tables

Suggested Readings

Castro CY, Ostrowski ML, Barrios R, et al. Relationship between Epstein-Barr virus and lymphoepithelioma-like carcinoma of the lung: a clinicopathologic study of 6 cases and review of the literature. Hum Pathol. 2001;32(8):863-872. [CrossRef] [PubMed]
 
Han AJ, Xiong M, Gu YY, Lin SX, Xiong M. Lymphoepithelioma-like carcinoma of the lung with a better prognosis. A clinicopathologic study of 32 cases. Am J Clin Pathol. 2001;115(6):841-850. [CrossRef] [PubMed]
 
Hayashi T, Haba R, Tanizawa J, et al. Cytopathologic features and differential diagnostic considerations of primary lymphoepithelioma-like carcinoma of the lung. Diagn Cytopathol. 2012;40(9):820-825. [CrossRef] [PubMed]
 
Liang Y, Wang L, Zhu Y, et al. Primary pulmonary lymphoepithelioma-like carcinoma: fifty-two patients with long-term follow-up. Cancer. 2012;118(19):4748-4758. [CrossRef] [PubMed]
 
Huang Y, Hsueh C, Ho SY, Liao CY. Lymphoepithelioma-like carcinoma of the lung: an unusual case and literature review. Case Rep Pulmonol. 2013;2013:143405. [PubMed]
 
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