A woman in her 70s presented with abnormal uterine bleeding. Imaging showed a 1.8 cm, friable cervical nodule compressing the cervical neck. Microscopic images and selected immunohistochemical stains are shown in Figure 1.
The correct answer is ...
Squamous cell carcinoma with a lymphoepithelioma-like morphologic pattern.
Histologic sections showed a cellular proliferation with infiltrative borders, arranged in solid, somewhat syncytial sheets and a vaguely lobular pattern. The tumor islands were separated by minimal intervening stroma. Close examination demonstrated a distinct subset of poorly differentiated epithelioid cells with irregular nuclear contours, increased nuclear-to-cytoplasmic ratio, vesicular chromatin, and variably prominent nucleoli. Mitotic activity was increased. In addition, a dense, stromal lymphocytic infiltrate was present within and around the tumor nests.
Immunohistochemical studies were performed to further characterize this neoplastic proliferation. The epithelioid cells were positive for keratin AE1/AE3 and P40, and demonstrated no immunoreactivity for chromogranin, myogenin, and synaptophysin. BRG1 and INI1 showed retained expression. The lymphoid infiltrate was highlighted by the CD45 immunostain.
Human papillomavirus (HPV) and Epstein–Barr virus (EBV) in situ hybridization (ISH) studies showed that the epithelioid proliferation was positive for HPV family 16 ISH (HPV types included in the panel: 16, 18, 31, 33, and 55). No reactivity was noted for HPV family 6 ISH (HPV types included in the panel: 6 and 11) and EBV ISH.
Based on these findings, a diagnosis of squamous cell carcinoma (SCC) with a lymphoepithelioma-like morphologic pattern was rendered. Lymphoepithelioma-like carcinoma is a variant of HPV-associated SCC of the uterine cervix, characterized by a dense lymphocytic stromal infiltrate.1 It is relatively rare and most of the literature is based on small case studies.2-6 It generally occurs at a younger age than “conventional” cervical SCC, with the average age at diagnosis being 52.9 years according to a literature review.5 However, a wide age range has been reported.3-6 Most of the patients described in the literature are multiparous and present with an exophytic mass.
The pathogenesis of lymphoepithelioma-like SCC of the uterine cervix has not been entirely elucidated. Few studies suggest EBV as an etiologic factor; however, a well-defined association between EBV and lymphoepithelioma-like SCC of the uterine cervix has not been established (1). Most of the evidence indicates an HPV-driven etiology.1-4,6 Limited data suggest a relatively better prognosis, compared to other SCCs of the uterine cervix.3,4
Microscopic examination shows sheets of poorly differentiated cells growing in a syncytial-like growth pattern. The individual cells have large nuclei with vesicular chromatin, prominent nucleoli, and poorly defined borders.2,4 Keratinization is typically absent. The neoplastic cells are admixed with a dense peritumoral and intratumoral inflammatory infiltrate comprised of lymphocytes, with a small subset of plasma cells.5,6 The infiltrating lymphocytes were demonstrated to be predominantly CD8 (+) T cells.5
Differential diagnosis of lymphoepithelioma-like carcinoma of the uterine cervix includes poorly differentiated adenosquamous carcinomas, formerly known as “glassy cell carcinomas.” On histopathologic examination, cells of this entity have distinct cell membranes and a high-grade cytomorphology with pleomorphic nuclei and abundant eosinophilic cytoplasm. In addition, the surrounding inflammatory infiltrate is rich in eosinophils and plasma cells in poorly differentiated adenosquamous carcinomas, in contrast to a predominance of lymphocytes in lymphoepithelioma-like carcinoma of the uterine cervix.6 Lymphoepithelioma-like SCC of the uterine cervix should also be distinguished from lymphomas involving the cervix, which are very rare. Additional studies such as flow cytometry can be utilized, if lymphoproliferative disorders remain within the differential diagnosis based on morphologic findings.
Burak Tekin, M.D.
Resident, Anatomic and Clinical Pathology
Amy Clayton, M.D.
Consultant, Anatomic Pathology
Associate Professor of Laboratory Medicine and Pathology
Mayo Clinic College of Medicine and Science