Cytokeratin-Negative Undifferentiated (Lymphoepithelial) Carcinoma of the Lacrimal Sac.

Epstein-Barr virus-associated undifferentiated (lymphoepithelial) carcinoma is a malignancy that most commonly arises in the nasopharynx but can also occur in other locations including the lacrimal sac. Generally, this tumor strongly expresses cytokeratin, making the diagnosis straightforward. In the absence of confirmatory immunohistochemistry, the diagnosis can be problematic, particularly for tumors arising in unusual locations. Only 3 cases arising in the lacrimal sac in association with Epstein-Barr virus have been reported in the English literature, and all showed typical pathologic findings. The authors report a fourth case, unique in that it showed negative immunostaining for all cytokeratins tested. The clue to the nature of the tumor came from identification of Epstein-Barr virus by in-situ hybridization and demonstration of tonofilaments by electron microscopy. This case demonstrates that a multimodal approach may be needed in the diagnosis of Epstein-Barr virus-associated carcinoma, especially when occurring in uncommon locations.

Hepatitis C virus induces abnormalities in surface and intraocular pressure: a comparative study.

OBJECTIVES: Various ocular lesions are associated with hepatitis C virus (HCV). Few studies have focused on untreated patients. This study aims to describe ocular lesions in untreated HCV-infected patients without ophthalmic symptoms by means of a comprehensive ophthalmologic examination. MATERIALS AND METHODS: Ninety-five consecutive naive HCV chronically infected patients and 54 controls (blood donors) were enrolled in a prospective, cross-sectional, single-center study. The following variables were analyzed: age, sex, HCV viral load and genotype, liver fibrosis, visual acuity, biomicroscopy of the anterior segment, lacrimal function (tear break-up time) and Schirmer's tests), posterior segment examination, and intraocular pressure. RESULTS: HCV-infected patients presented an almost four times higher risk of lacrimal function involvement by tear break-up time [odds ratio (OR)=3.76; 95% confidence interval (CI) 1.75-8.04, P=0.001] and Schirmer's test (OR=4.17; 95% CI 1.83-9.50, P=0.001) than the controls. The chances of palpebral biomicroscopic lesions (blepharitis) were also higher (OR=3.21; 95% CI 1.49-6.94, P=0.003). Mean tonometry was higher in HCV patients (right eye 14.4±2.3 vs. 12.2±1.5, P<0.001 and left eye 14.5±2.3 vs. 12.0±1.4, P<0.001). CONCLUSION: Naive HCV patients even with no ophthalmic complaints presented a greater prevalence of lacrimal function abnormalities and a higher frequency of blepharitis compared with the control group. As never formerly described, intraocular pressure in HCV patients was higher than that in controls.

Hepatitis C virus infection in ocular adnexal lymphomas.

OBJECTIVE: To assess the influence of hepatitis C virus (HCV) infection on disease appearance and outcome of ocular adnexal non-Hodgkin lymphoma (ONHL). DESIGN: Retrospective comparative study (from January 1, 1992, through December 31, 2006). METHODS: The medical records of 129 patients with ONHL were retrospectively reviewed. All the patients were tested serologically for the presence of HCV infection. Patients were divided into 2 groups according to the presence or absence of HCV infection. MAIN OUTCOME MEASURES: Prevalence of HCV infection, staging to evaluate the extent of disease at the onset, and clinical outcome data on overall and disease-free survival. RESULTS: The prevalence of HCV infection among the patients with ONHL was 17.8%. Seropositivity for HCV infection was significantly associated with extraorbital lymphoma at the onset (P = .006). High prevalence of mucosa-associated lymphoid tissue disease (79.8%) was registered. Protocol therapy included radiotherapy and chemotherapy, depending on the stage of the disease. Complete remission was achieved in 99 patients (76.7%). A total of 23.6% of patients with HCV-seronegative status and 21.7% of those with HCV-seropositive status experienced relapse of the lymphomatous disease. No significant differences in the 5-year overall survival and disease-free survival between the 2 groups were observed. CONCLUSIONS: Prevalence of HCV infection in patients with ONHL is a relevant issue, accounting for 17.8% of the examined patients. Infection with HCV may influence the initial appearance of ONHL because it is associated with more widespread disease at the onset. However, the overall and disease-free survival of the infected patients are not statistically different than that of patients who are not infected.

The role of infectious agents in the etiology of ocular adnexal neoplasia.

Given the fact that infectious agents contribute to around 18% of human cancers worldwide, it would seem prudent to explore their role in neoplasms of the ocular adnexa: primary malignancies of the conjunctiva, lacrimal glands, eyelids, and orbit. By elucidating the mechanisms by which infectious agents contribute to oncogenesis, the management, treatment, and prevention of these neoplasms may one day parallel what is already in place for cancers such as cervical cancer, hepatocellular carcinoma, gastric mucosa-associated lymphoid tissue lymphoma and gastric adenocarcinoma. Antibiotic treatment and vaccines against infectious agents may herald a future with a curtailed role for traditional therapies of surgery, radiation, and chemotherapy. Unlike other malignancies for which large epidemiological studies are available, analyzing ocular adnexal neoplasms is challenging as they are relatively rare. Additionally, putative infectious agents seemingly display an immense geographic variation that has led to much debate regarding the relative importance of one organism versus another. This review discusses the pathogenetic role of several microorganisms in different ocular adnexal malignancies, including human papilloma virus in conjunctival papilloma and squamous cell carcinoma, human immunodeficiency virus in conjunctival squamous carcinoma, Kaposi sarcoma-associated herpes virus or human herpes simplex virus-8 (KSHV/HHV-8) in conjunctival Kaposi sarcoma, Helicobacter pylori (H. pylori,), Chlamydia, and hepatitis C virus in ocular adnexal mucosa-associated lymphoid tissue lymphomas. Unlike cervical cancer where a single infectious agent, human papilloma virus, is found in greater than 99% of lesions, multiple organisms may play a role in the etiology of certain ocular adnexal neoplasms by acting through similar mechanisms of oncogenesis, including chronic antigenic stimulation and the action of infectious oncogenes. However, similar to other human malignancies, ultimately the role of infectious agents in ocular adnexal neoplasms is most likely as a cofactor to genetic and environmental risk factors.

Assessment of the role of hepatitis C, Helicobacter pylori and autoimmunity in MALT lymphoma of the ocular adnexa in 45 Austrian patients.

INTRODUCTION: A recent series from Italy has suggested a pathogenic link between hepatitis C virus and MALT lymphoma of the ocular adnexa. The hypothesis of our study was to prove this concept in Austrian patients with MALT lymphoma of the ocular adnexa. MATERIALS AND METHODS: A total of 45 patients presenting with MALT lymphoma of the ocular adnexa were assessed for the presence of infection with hepatitis A, B and C. Furthermore, extensive staging to evaluate the extent of disease along with analysis of Helicobacter pylori-infection, the presence or absence of autoimmune diseases (AD) and assessment of MALT-lymphoma specific genetic changes was performed. RESULTS: Only 2/45 (4%) patients were tested positive for hepatitis C, while 10/45 (22%) had an underlying AD and 15/39 (38%) had HP infection. Chromosomal aberrations were detected in 19 (54%) of 35 patients analyzed. Disseminated disease was a significant risk factor for relapse (p=0.014). DISCUSSION: Our series suggests that infection with hepatitis C is not a significant contributor to the pathogenesis of ocular adnexal MALT lymphoma in the Austrian population, while a substantial proportion of these patients suffer from autoimmune conditions.

Human papillomavirus: cause of epithelial lacrimal sac neoplasia?

PURPOSE: Epithelial tumours of the lacrimal sac are rare but important entities that may carry grave prognoses. In this study the prevalence and possible role of human papillomavirus (HPV) infection in epithelial tumours of the lacrimal sac were evaluated. METHODS: Five papillomas and six carcinomas of the lacrimal sac were investigated for the presence of HPV using the polymerase chain reaction (PCR) technique. Fifteen specimens of dacryocystitis were included in the PCR reactions as controls. Furthermore, DNA in situ hybridization (ISH) and RNA ISH were performed. RESULTS: Low-risk HPV types 6 or 11 were identified in all four lacrimal sac papillomas suitable for PCR analysis and in situ hybridization. Four of six lacrimal sac carcinomas harboured HPV. One carcinoma was positive for HPV 11 only, two carcinomas had concomitant infection with HPV 6 or 11 and high-risk HPV 16, and the remaining carcinoma was positive for HPV 16. All specimens of dacryocystitis were betaglobin-positive and HPV-negative. Using DNA ISH, two papillomas and a single carcinoma showed evidence for vegetative HPV 11 DNA replication, whereas no HPV 16 DNA replication was found in the five carcinomas tested. HPV 11 RNA was demonstrated in two papillomas. CONCLUSIONS: By analysing 11 epithelial lacrimal sac papillomas and carcinomas using PCR, DNA ISH and RNA ISH, we found HPV DNA in all investigated transitional epithelium tumours of the lacrimal sac. HPV RNA was present in two of eight epithelial lacrimal sac tumours positive for HPV DNA. As RNA degrades fast in paraffin-embedded tissue, only a small fraction of DNA-positive tumours can be expected to be RNA-positive. We therefore suggest that HPV infection is associated with the development of lacrimal sac papillomas and carcinomas.

Natural killer/T-cell lymphoma with ocular and adnexal involvement.

PURPOSE: To review the clinical, radiological, and histopathologic features in 8 patients with natural killer/T-cell lymphoma (NKTL) involving the orbit and/or ocular adnexa, and to describe the responses of these patients to various treatment regimens. DESIGN: Retrospective observational case series. PARTICIPANTS: Eight patients (5 male, 3 female) with NKTL involving the orbit and/or ocular adnexa were identified from 1999 through 2005. The mean age at presentation was 45 years (range, 26-65). METHODS: We retrospectively identified patients with NKTL of the ocular adnexa treated in the authors' medical centers from 1999 through 2004 using computerized diagnostic index retrieval. The clinical records and radiologic studies were analyzed to define modes of presentation and progression, response to therapy, and areas of anatomic involvement. Histopathologic findings, including the presence of CD3, CD56, and Epstein-Barr virus-encoded mRNA in each patient, were reviewed. MAIN OUTCOME MEASUREMENTS: Time of survival from presentation to last known follow-up and tumor-related death. RESULTS: Four of the 8 patients (50%) with NKTL involving the orbit or ocular adnexa had systemic involvement at presentation. Five of the 8 patients (62.5%) had concurrent sinonasal involvement, whereas 3 (37.5%) had orbital involvement alone. All lesions demonstrated CD3, CD56, and/or Epstein-Barr virus positivity on immunopathology studies. Therapy consisted of various chemotherapeutic regimens typically employed in the treatment of non-Hodgkins lymphoma, steroids, surgical intervention, and radiation. Seven (87.5%) patients died 5 weeks to 13 months after presentation, and 1 (12.5%) is alive without disease (5-year follow-up). CONCLUSIONS: Natural killer/T-cell orbital lymphoma is a rare Epstein-Barr virus-associated neoplasm that may occur with or without associated sinonasal involvement. Our series, the largest cohort reported to date, demonstrates the high lethality of this condition despite aggressive conventional therapy, suggesting that new treatment options should be considered early in the course of treatment of patients with this disorder.

Schneiderian papillomas and carcinomas: a review.

The ectodermally derived Schneiderian mucosa gives rise to an extremely varied collection of benign and malignant neoplasms. Prototypical of these are the Schneiderian papillomas (inverted, fungiform, and cylindrical cell) and their malignant counterparts. Human papilloma virus (HPV) is currently the leading candidate as a cofactor in the pathogenesis of the papillomas. Carcinomas arise in association with the papillomas in about a 10% frequency. The carcinomas may be synchronous or metachronous. Recurrences of the papillomas are the bane of surgeons. The magnitude of the recurrences is directly proportional to the completeness of removal with the best results obtained by techniques that afford the best operative exposure. A comparison of results by different surgical procedures is presented. Histologic features sought to predict recurrences or malignant transformation have, by and large, not been helpful. Keratinization and hyperkeratosis in papillomas, however, are suggested to be sufficiently ominous as to warrant further study.

Analysis of cytomegalovirus infection and replication in acinar epithelial cells of the rat lacrimal gland.

PURPOSE: The objectives of this investigation were threefold: to advance understanding of the nature and impact of herpesvirus infection in the lacrimal gland; to determine the influence of gender and sex hormones on viral infectivity and replication capacity in lacrimal tissue; and to compare the susceptibilities of lacrimal, submandibular, and parotid cells to viral invasion. METHODS: Acinar epithelial cells were isolated from lacrimal or salivary glands from intact, orchiectomized, ovariectomized, or sham-operated rats, cultured on Matrigel in serum-free media, and briefly exposed to rat cytomegalovirus (RCMV). Cells were then incubated for varying time intervals, and RCMV titers and secretory component (SC) levels in media or cell extracts were measured by plaque assay or radioimmunoassay. Exocrine glands also were obtained from rats after RCMV inoculation in vivo and were analyzed for viral infection. RESULTS: These findings demonstrated that RCMV invades the rat lacrimal gland after intravenous or intraperitoneal viral inoculation; RCMV infects and undergoes a time-, dose-, strain-, and gender-dependent replication in acinar epithelial cells from rat lacrimal tissue; the magnitude of RCMV replication in acinar epithelial cells in vitro may, in fact, induce an acute increase in the cellular production of SC; and the extent of viral replication in lacrimal and salivary gland epithelial cells displays distinct, tissue-specific variations. CONCLUSIONS: The herpesvirus RCMV invades and replicates in acinar epithelial cells from the rat lacrimal gland. The magnitude of the viral infection may be significantly influenced by gender and alterations in the hormonal environment.