Anatomic pathology selected abstracts

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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; Rachel Stewart, DO, PhD, assistant professor, Department of Pathology and Laboratory Medicine, University of Kentucky, Lexington; Nicole Panarelli, MD, associate professor of pathology, Albert Einstein College of Medicine, Montefiore Medical Center; and Shaomin Hu, MD, PhD, pathology resident, Albert Einstein College of Medicine, Montefiore Medical Center.

Link between nuclear β-catenin localization and CTNNB1 gene mutation

July 2019—Although the majority of low-grade, early stage endometrial cancer patients have good survival rates with surgery alone, patients who recur tend to do poorly. Identifying patients at high risk of recurrence who would benefit from adjuvant treatment or more extensive surgical staging would improve individualized care for endometrial cancer patients. CTNNB1 (encodes β-catenin) mutations identify a subset of low-grade, early stage endometrial cancer patients at high risk of recurrence. CTNNB1 exon 3 mutation is classically associated with translocation of the β-catenin protein from the membrane to the nucleus and activation of Wnt/β-catenin signaling. Given the clinical utility of identifying endometrial carcinomas with CTNNB1 mutation, the authors conducted a retrospective analysis to determine if immunohistochemistry could act as a surrogate for CTNNB1 gene sequencing. They examined 345 endometrial carcinoma patients who had undergone next-generation sequencing. Immunohistochemical localization of β-catenin was determined for 53 of 63 CTNNB1 exon 3 mutant tumors for which tissue was available and a subset of wild-type tumors. Nuclear localization of β-catenin had 100 percent specificity in distinguishing CTNNB1 mutant from wild-type tumors, but sensitivity was lower (84.9 percent). Nearly half of CTNNB1 mutant cases had only five to 10 percent of tumor cells with β-catenin nuclear localization. The concordance between pathologists blinded to mutation status in assessing nuclear localization was 100 percent. The extent of β-catenin nuclear localization was not associated with a specific CTNNB1 gene mutation, tumor grade, presence of nonendometrioid component, or specific concurrent gene mutations in the tumor. For comparison, nuclear localization of β-catenin was more diffuse in desmoid fibromatosis, a tumor also associated with CTNNB1 mutation. Therefore, nuclear localization of β-catenin assessed by immunohistochemistry does not detect all endometrial cancers with CTNNB1 gene mutation. The extent of nuclear localization may be tumor-type dependent. For endometrial cancer, immunohistochemistry could be an initial screen, with CTNNB1 gene sequencing employed when nuclear localization of β-catenin is absent.

Kim G, Kurnit KC, Djordjevic B, et al. Nuclear β-catenin localization and mutation of the CTNNB1 gene: a context-dependent association. Mod Pathol. 2018;31:1553–1559.

Correspondence: Dr. Russell Broaddus at rbroaddus@mdanderson.org

Relationship between IDO and PD-L1 in breast cancer

The immune inhibitory enzyme indoleamine 2,3-dioxygenase (IDO) has been associated with immune evasion in numerous malignancies and may mark these cancers as susceptible to anti-IDO therapies. The authors conducted a study in which they addressed IDO expression in breast cancers, examined the relationship between IDO and PD-L1, and investigated IDO fidelity across breast cancer primaries and metastases. IDO and PD-L1 expression was assessed in tissue microarrays containing 242 invasive primary breast cancers, 20 nodal metastases, and 19 distant metastases. IDO and PD-L1 were scored by extent in the tumor cells and immune infiltrate. Tumor IDO staining was seen in 14 percent of primaries, including 38 percent of triple-negative cancers. IDO immune cell staining was seen in 14 percent of primaries and 29 percent of triple-negative cancers. Tumoral IDO and PD-L1 co-expression was seen in eight percent of primaries, including 70 percent of tumoral PD-L1–positive cases. Immune IDO and PD-L1 co-expression was identified in 14 percent of primaries, including 48 percent of immune PD-L1–positive cases. Tumoral and immune cell IDO was conserved in 94 percent of matched primaries and metastases. In summary, IDO expression is common among high-grade, triple-negative breast cancers and is frequently associated with PD-L1 co-expression, suggesting that IDO might be a mechanism of anti-PD-1/PD-L1 immunotherapy resistance and that dual therapy may be of utility. Tumoral and immune cell IDO expression shows fidelity between primary and metastatic sites in treatment-naïve cancers, arguing against IDO as an independent driver of metastatic spread. Clinical trials are needed to assess the efficacy of IDO inhibition relative to IDO expression and its possible role in combination with anti-PD-1/PD-L1 immunotherapy.

Dill EA, Dillon PM, Bullock TN, et al. IDO expression in breast cancer: an assessment of 281 primary and metastatic cases with comparison to PD-L1. Mod Pathol. 2018;31:1513–1522.

Correspondence: Dr. Anne M. Mills at amm7r@virginia.edu

Fibrosis in liver biopsies of patients with heart failure undergoing heart transplant evaluation

Liver biopsies are commonly performed in heart transplant candidates to confirm congestive hepatopathy and assess the degree of fibrosis. Heterogeneity of fibrosis is frequent in congestive hepatopathy (CH), making it difficult to stage fibrosis. The authors conducted a study in which they evaluated the prevalence of heterogeneity of fibrosis and nodular regenerative hyperplasia in liver biopsies with CH secondary to heart failure. They reviewed 50 liver biopsies with CH secondary to heart failure. Fibrosis was scored, using trichrome stain, as stage zero for no fibrosis, stage one for zone three fibrosis, stage two for zone three and portal fibrosis, stage three for bridging fibrosis, and stage four for cirrhosis. Stages three and four were classified as advanced fibrosis. A predominant pattern of fibrosis and a secondary pattern of fibrosis, defined as a different stage of fibrosis seen in at least 10 percent of the biopsy material, if present, were recorded. A biopsy was considered to show heterogeneous fibrosis if there was at least a two-stage difference between the predominant and secondary patterns. Thirteen (26 percent) biopsies showed heterogeneous fibrosis. Sixteen (32 percent) biopsies showed some evidence of advanced fibrosis—five had uniform advanced fibrosis, four had predominant pattern of advanced fibrosis, and advanced fibrosis was focal in seven biopsies from six patients. Nodular regenerative hyperplasia-type changes were seen in nine of 50 (18 percent) biopsies. The authors concluded that this study showed heterogeneous fibrosis in the liver biopsy of a quarter of patients with CH due to heart failure, highlighting the limitations of fibrosis assessment in the biopsies, and suggested that correlation with complete clinical information is essential for making management decisions.

Dhall D, Kim SA, McPhaul C, et al. Heterogeneity of fibrosis in liver biopsies of patients with heart failure undergoing heart transplant evaluation. Am J Surg Pathol. 2018;42​(12):1617–1624.

Correspondence: Dr. Deepti Dhall at deepti.dhall@cshs.org

IHC evaluation of 5-hmC to distinguish malignant pleural mesothelioma from benign mesothelial proliferations

Distinguishing benign mesothelial proliferations from malignant mesothelioma remains a diagnostic challenge. The sequential use of BAP1 immunohistochemistry (IHC) and CDKN2A FISH is specific for diagnosing mesothelioma, but FISH is costly and time-consuming. Early data indicate that mesothelioma shows extensive loss of nuclear 5-hydroxymethylcytosine (5-hmC). The authors studied 49 cases of mesothelioma—17 epithelioid mesotheliomas, 22 biphasic mesotheliomas, and 10 sarcomatoid mesotheliomas—and 23 benign mesothelial proliferations. They used a 5-hmC single IHC stain, CAM5.2/5-hmC double IHC stain, and BAP1 IHC. Two of the three authors estimated the extent of 5-hmC loss using the 5-hmC single stain and CAM5.2/5-hmC double stain. The extent of nuclear 5-hmC loss was definitively quantitated in at least 1,000 cells per case. Mean nuclear 5-hmC loss in mesothelioma was significantly greater (84 percent) than in benign mesothelial proliferations (four percent; P < .0001). Using 5-hmC loss in more than 50 percent of tumor nuclei to define the diagnosis of mesothelioma, 5-hmC IHC showed sensitivity of 92 percent and specificity of 100 percent. An immunopanel including 5-hmC and BAP1 IHC achieved sensitivity of 98 percent and specificity of 100 percent. The authors concluded that extensive nuclear 5-hmC loss is sensitive and specific for mesothelioma in the differential diagnosis with benign mesothelial proliferations. For challenging mesothelial lesions, IHC studies showing extensive 5-hmC loss or BAP1 loss indicate a diagnosis of mesothelioma, precluding the need for CDKN2A FISH in a considerable number of cases.