Editors: Rouzan Karabakhtsian, MD, PhD, professor of pathology and director of the Women’s Health Pathology Fellowship, Albert Einstein College of Medicine, Montefiore Medical Center, Bronx, NY; Shaomin Hu, MD, PhD, staff pathologist, Cleveland Clinic; S. Emily Bachert, MD, breast pathology fellow, Brigham and Women’s Hospital, Boston; and Amarpreet Bhalla, MD, assistant professor of pathology, Albert Einstein College of Medicine, Montefiore Medical Center.
Morphology of tumor and nontumor liver tissue in hepatocellular carcinoma patients treated with nivolumab
September 2021—Nivolumab is an immune checkpoint inhibitor approved for treating many types of cancer, including hepatocellular carcinoma (HCC). Liver injury is a known complication in patients treated with nivolumab for nonliver tumors. The morphologic changes to tumor and nontumor liver have not been well-characterized in HCC patients. Therefore, the authors conducted a study to characterize morphologic changes in tumor and nontumor liver tissue from patients who underwent partial or total hepatectomy following nivolumab therapy for HCC. They identified 20 patients who underwent partial hepatectomy or liver transplantation after receiving nivolumab for the disease. The authors obtained demographics, laboratory values, and imaging results from patients’ medical records. They evaluated all available slides from resection specimens for tumor necrosis, tumor-infiltrating lymphocytes, and features of liver injury. The study included 16 male and four female patients, who were a median age of 56 years. The underlying liver disease was hepatitis B virus in 10, hepatitis C virus in six, and unknown/other in four. Twelve patients were treated with nivolumab in the neoadjuvant setting, and eight were treated with nivolumab, usually with other therapies, before undergoing liver transplantation. On review of resection specimens, three patients, all of whom were from the neoadjuvant group, demonstrated marked treatment response attributable to nivolumab. Tumor-infiltrating lymphocytes were present in 17 of 20 cases. One case that showed treatment response in the neoadjuvant group demonstrated non-necrotizing granulomas and prominent bile duct intraepithelial lymphocytes in the nontumor liver. One case from the transplant group showed bile duct damage and prominent ductular reaction after long-term nivolumab therapy (32 doses). The authors’ findings indicate that nivolumab is effective in a subset of patients, including in the neoadjuvant setting. Granulomas and bile duct intraepithelial lymphocytes are rare findings in patients treated with nivolumab, but they may indicate potential response to therapy. Bile duct damage and ductular reaction may be manifestations of long-term nivolumab therapy. Future prospective and longitudinal studies with pretreatment tumor biopsies may help identify patients likely to respond to immune checkpoint inhibitor therapy and further characterize patterns of ICI-related liver injury.
Simoes CC, Thun SW, Fiel MI, et al. Morphology of tumor and nontumor tissue in liver resection specimens for hepatocellular carcinoma following nivolumab therapy. Mod Pathol. 2021;34:823–833.
Correspondence: Dr. Stephen C. Ward at stephen.ward@mountsinai.org
Diagnostic value of cell blocks in urine cytopathology: a pilot study
The utility of cell block preparation is well established in cytopathology. Yet even though 23.3 percent of College of American Pathologists-accredited laboratories use cell blocks with liquid-based preparations on urine cytology cases, few studies addressing their performance have been conducted. To determine the usefulness of cell blocks, the authors conducted a retrospective review of urine cytology specimens that underwent cell block preparation. They identified 27 urine cytology cases at their institution involving ThinPrep and cell block preparation between 2016 and 2020 and compiled clinical history and follow-up data on patients. Two pathologists and two cytotechnologists performed a blinded review of ThinPrep alone and ThinPrep with cell blocks. Diagnoses were rendered in accordance with The Paris System for Reporting Urine Cytology. Blood and acute inflammation were common in patients who underwent cell block preparation. The authors found that cell block preparation upgraded the diagnosis in 26 percent (seven of 27) of cases. The maximum utility of cell block preparation was seen in indeterminate cases in which 60 percent (six of 10) were upgraded, including 71 percent (five of seven) of atypical urothelial cells and 30 percent (one of three) of suspicious for high-grade urothelial carcinomas (HGUC). One (one of 12; eight percent) case diagnosed as negative for HGUC with ThinPrep was diagnosed as low-grade urothelial neoplasia via cell block. The authors concluded that their results demonstrate that adjunct use of cell block preparation aids in a definitive diagnosis in the atypical urothelial cell category and may be helpful in cases with cell clusters or tissue fragments and cases suspicious for HGUC. Additional correlation studies are warranted to further understand the utility of cell blocks in urine cytology.
Wilson BL, Russel D, Evans SK, et al. Cell blocks in urine cytopathology: Do they add value to the diagnosis? A pilot study. J Am Soc Cytopathol. 2021;10(1):47–55.
Correspondence: Dr. Tanupriya Agrawal at tanupriya_agrawal@urmc.rochester.edu
Screening for AIN in women with a history of CIN or cancer
High-risk human papillomavirus has been identified in the pathogenesis of anal cancer. The authors conducted a study to assess the prevalence of abnormal anal cytology and human papillomavirus (HPV) in women 40 years and older who had a history of high-grade cervical squamous intraepithelial lesion (SIL) or cancer and to estimate the prevalence of anal intraepithelial neoplasia (AIN) using cytology as the primary screening modality. Anal cytology with HPV-DNA testing was performed. All patients with abnormal anal cytology were referred for high-resolution anoscopy (HRA), and abnormal lesions were biopsied and treated if confirmed pathologically. Abnormal anal cytology correlated with HPV status, HRA findings, and clinical and demographic characteristics. Of 317 women who completed the study, 96 (30.3 percent) had abnormal anal cytology (high-grade SIL, 12.5 percent; low-grade SIL, 19.8 percent; atypical squamous cells, cannot exclude high-grade SIL, 6.3 percent; atypical squamous cells of undetermined significance, 61.5 percent) and 101 (31.9 percent) were HPV-DNA positive. A significant association between abnormal cytology results and presence of high-risk HPV was found. Of the 96 patients with abnormal cytology, 30 (31.3 percent) had biopsy-proven AIN on HRA, representing 9.5 percent of the total patient cohort. Ten (33.3 percent) patients in the latter group had low-grade AIN and 20 (66.7 percent) had high-grade AIN. Older age and smoking were significant risk factors for abnormal anal cytology. The authors concluded that women 40 years and older who have a history of high-grade cervical SIL or cancer have a high rate of AIN. Therefore, screening for anal cancer should be considered in this patient population. The optimal screening approach should be addressed in future studies.
Wohlmuth C, Ghorab Z, Shier M, et al. Cytology-based screening for anal intraepithelial neoplasia in women with a history of cervical intraepithelial neoplasia or cancer. Cancer Cytopathol. 2021;129(2):140–147.
Correspondence: Dr. Danielle Vicus at danielle.vicus@sunnybrook.ca
Varicella zoster virus infection of the upper gastrointestinal tract
Reactivation of latent varicella zoster virus may be limited to a dermatome or involve multiple organs, including the gastrointestinal tract. Although gastrointestinal manifestations of disseminated zoster have been likened to those of herpes simplex virus (HSV), histologic features of varicella zoster virus (VZV)-related injury to the tubular gut are not well documented. The authors performed a study to describe the clinicopathologic features of VZV-related gastrointestinal injury. They identified six patients with VZV infection. All infections involved the upper gastrointestinal tract, affecting the esophagus (n = 3), stomach (n = 2), or both (n = 1). All patients were immunocompromised adults with hematologic malignancies (n = 5) or a heart transplant (n = 1). Three of the patients with hematologic malignancies had received stem cell transplants. Five patients had cutaneous and gastrointestinal zoster and one had gastrointestinal disease alone. The authors found notable differences when comparing the study participants who had VZV with 14 cases of HSV-related esophagitis used as controls. Among the findings was that VZV caused hemorrhagic ulcers with nodularity or erythema, whereas HSV produced round, shallow ulcers on a background of nearly normal mucosa (P = .01). VZV-related ulcers also featured fibrin-rich, pauci-inflammatory exudates, in contrast to the macrophage-rich exudates of HSV (P = .003). The cytopathic changes of VZV were present at all levels of the squamous epithelium, especially in a peripapillary distribution. In contrast, HSV inclusions were located in the superficial layers (P = .003) and detached keratinocytes. Unlike HSV, VZV involved the stomach, producing hemorrhage accompanied by striking apoptosis in the deep glands. The authors concluded that VZV produces unique patterns of gastrointestinal injury that facilitate its diagnosis. Recognition of gastrointestinal VZV infection is important because the infection heralds potentially life-threatening disseminated disease.
Mostyka M, Shia J, Neumann WL, et al. Clinicopathologic features of varicella zoster virus infection of the upper gastrointestinal tract. Am J Surg Pathol. 2021;45(2):209–214.
Correspondence: Dr. M. Mostyka at mam9714@nyp.org
Comparison of immune checkpoint inhibitor-induced upper GI tract inflammation to other entities
Immune checkpoint inhibitor therapies are associated with multi-organ immune-related adverse events. Although colonic mucosal changes have been described, inflammatory changes in the upper gastrointestinal tract incited by immune checkpoint inhibitors (ICI) have not been well characterized. The authors conducted a study to investigate morphologic and immunologic changes in the upper gastrointestinal tract incited by ICI therapy. They compared the morphology and immune cell phenotype of gastric and duodenal biopsies from patients treated with anti-cytotoxic T-lymphocyte–associated protein 4 (CTLA-4) or anti-programmed death receptor-1/programmed death ligand-1 (PD-1/PD-L1) antibodies with biopsies from patients with Helicobacter pylori gastritis or celiac disease and normal controls. Gastric biopsies from patients on ICIs showed chronic gastritis mimicking H. pylori gastritis. However, ICI-induced gastritis demonstrated greater numbers of CD8+ intraepithelial lymphocytes, less lamina propria inflammation, fewer plasma cells and CD20+ B cells, fewer lymphoid aggregates, and a reduced CD4:CD8 ratio in the lamina propria and epithelial layer. There were no differences between anti-CTLA-4– and anti-PD-1/PD-L1–associated gastritis, except for more lymphoid aggregates in the latter. Duodenal biopsies from patients on ICIs revealed chronic duodenitis with villous blunting, mimicking celiac disease. Compared with celiac disease, ICI-associated duodenitis demonstrated a higher prevalence of neutrophilic infiltrates and erosions, increased lamina propria CD3 and CD8 T cells, and a reduced CD4:CD8 ratio. Upper gastrointestinal tract biopsies were more inflamed than concomitant colonic biopsies in the majority of patients. The authors concluded that the morphologic and immunophenotypic distinctions between ICI-associated upper gastrointestinal tract injuries and common infectious and autoimmune diseases may provide useful discriminators when clinicians are confronted with gastric and duodenal inflammatory changes in patients receiving ICI therapy.
Irshaid L, Robert ME, Zhang X. Immune checkpoint inhibitor–induced upper gastrointestinal tract inflammation shows morphologic similarities to, but is immunologically distinct from, Helicobacter pylori gastritis and celiac disease. Arch Pathol Lab Med. 2021;145(2):191–200.
Correspondence: Dr. Xuchen Zhang at xuchen.zhang@yale.edu