Cytological features of lung adenocarcinoma with massive lymphocyte infiltration.

Adenocarcinoma with massive lymphocyte infiltration is a rare pulmonary neoplasm with few reported cases. It seems to have a better outcome than conventional adenocarcinomas, but it is still not clear if it constitutes a specific clinicopathological entity. We report a case in which cytological studies were available. The small size of the tumor, abundant lymphocyte population, well-differentiated morphology of the neoplasm and scarcity of atypical cells resulted in a difficult cytological diagnosis. This entity should be considered when evaluating pulmonary lesions with abundant lymphocytes. Not all carcinomas with prominent lymphoid stroma show the high-grade, pleomorphic morphology of lymphoepithelioma-like carcinomas.

Introduction

Pulmonary adenocarcinoma with massive lymphocyte infiltration was first reported in 2003 by Minami et al.[1] The number of reported cases is low and it is still not clear if it constitutes a specific clinicopathological entity. Similarly, as it occurs with other neoplasms showing extensive lymphocyte infiltration, this adenocarcinoma variant seems to have a better outcome than the conventional ones.[12] Despite prominent lymphoid stroma, it shows no relation with Epstein–Barr virus (EBV). We report a case in which cytological studies were available. The prominent lymphocyte population and well-differentiated morphology of the neoplasm resulted in diagnostic difficulties.

Case Report

The patient, a 77-year-old man, was being evaluated for a solitary, slowly growing, pulmonary nodule in the left lower lobe. On computed tomography examination, the lesion measured less than 2 cm, showed ill-defined limits and was located peripherally in the upper part of the lobe, without pleural involvement. The patient was a smoker with ischemic heart disease. Cytological material was obtained by transthoracic fine-needle aspiration and during an intraoperative consultation procedure. Samples showed a similar image consisting of numerous lymphoid cells admixed with epithelial clusters. Most lymphocytes were small, mature and were accompanied by lymphoglandular bodies, a few plasma cells and macrophages without granuloma formation. Epithelial groups had a variable appearance. Some of them were small, monolayered and composed of normal looking pneumocytes. In contrast, a few groups exhibited larger epithelial cells with nuclear pleomorphism and nucleoli [Figure 1a, b]. Due to the abundance of lymphocytes and relative scarcity of atypical cells that were accompanied by benign looking ones, a cytological diagnosis of suspicious for malignancy was made. Similar problems occurred during the intraoperative procedure. The tumor measured 1.5 cm, and frozen sections revealed prominent lymphoid stroma, fibrosis and distorted glands without clear evidence of malignancy. Scrapping cytology samples showed a similar image to that seen on aspiration. Lobectomy with regional lymph node resection was performed. The tumor measured 1.5 cm, had a soft consistency and was ill defined, with a pale brown color, difficult to differentiate from the surrounding parenchyma. It consisted of variable sized glands, some of them irregular, immersed in a prominent lymphoid stroma with follicle formation. Neoplastic cells were cuboid to columnar with moderate atypia and low mitotic index [Figure 1c, d]. No pleural, lymph node or bronchial involvement was observed. Immunohistochemistry showed characteristic features of primary lung adenocarcinoma with expression of cytokeratin 7, thyroid transcription factor-1 and napsin A. There was no expression of cytokeratin 20, thyroglobulin, or latent membrane protein 1. Lymphocytes were a mixture of CD3 and CD20, the latter constituting small follicular structures with no bcl-2 expression. Presence of EBV was analyzed on paraffin-embedded tissue by in situ hybridization for EBV-encoded small RNA-1 with negative results.

Figure 1

(a) Two atypical, large epithelial cells are seen along with numerous lymphocytes and a few macrophages (Diff-Quik, ×400); (b) In addition to small lymphocytes, a monolayered cluster of atypical epithelial cells is evident. A large, naked nucleus with nucleolus is seen at the bottom (Diff-Quik, ×400); (c and d) Histology reveals irregular glands composed of cuboidal to columnar cells in a prominent lymphoid stroma in which lymphoid follicles are present (H and E, ×200)

Discussion

The present case illustrates a rare morphological variant of pulmonary adenocarcinoma that resulted in diagnostic difficulties during needle aspiration and later during intraoperative consultation. In the previous reports concerning nine patients, no mention is made of preoperative cytology or biopsy.[12]

The diagnostic difficulties seen in the present case were due to the small size of the tumor, abundant lymphocyte population, well-differentiated morphology of the neoplasm and scarcity of atypical cells. Slight degrees of chronic inflammation are commonly observed in the stroma of carcinomas, but rarely in such intensity as to create diagnostic problems.

On pulmonary cytology, it is advised that a diagnosis of malignancy in a background of inflammation should be made with extreme caution. Acute inflammation with abscess formation is well known to occur in squamous cell carcinoma, but a prominent lymphoid component is rarely seen in pulmonary carcinomas. If a neoplasm shows evident architectural and cytological atypia, associated chronic inflammation is not an important diagnostic problem. However, in well-differentiated adenocarcinomas with scarce pleomorphism, it may raise the possibility of an inflammatory lesion with reactive pneumocyte atypia, especially if the epithelial component is scarce.

Most carcinomas with abundant lymphoid stroma belong to the category of lymphoepithelioma-like carcinomas. These resemble nasopharyngeal carcinoma and are characterized by a high-grade, undifferentiated morphology and relation with EBV. The cytological features of lymphoepithelioma-like carcinoma of the lung have been reported as showing evident signs of malignancy.[34] In contrast, well differentiated morphology with massive lymphocyte infiltration, as seen in the present case, may be scarce. This entity should be considered when evaluating pulmonary lesions with abundant lymphocytes. Not all carcinomas with prominent lymphoid stroma show the high-grade, pleomorphic morphology of lymphoepithelioma-like carcinomas.