Anatomic pathology Abstracts

Editors: Rouzan Karabakhtsian, MD, PhD, professor of pathology, Albert Einstein College of Medicine, Montefiore Medical Center, Bronx, NY; Rachel Stewart, DO, PhD, molecular genetic pathology fellow, University of Utah/ARUP Laboratories, Salt Lake City; 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.

Clinical and molecular analyses of neuroendocrine carcinomas of breast

July 2018—Neuroendocrine breast carcinomas represent a rare subtype of breast cancer. Their definition, prevalence, and prognosis remain controversial, as reported in the literature. The 2012 World Health Organization classification of breast cancer categorizes neuroendocrine carcinomas into three morphologically distinct subtypes: well-differentiated neuroendocrine tumors, poorly differentiated neuroendocrine carcinomas, and invasive breast carcinomas with neuroendocrine differentiation.

The authors conducted a study to gain insight into the clinical, morphologic, phenotypic, and molecular features of 47 neuroendocrine breast carcinomas. They performed targeted next-generation sequencing by an AmpliSeq 22 cancer gene hotspot panel and the Prosigna assay on 42 of 47 and 35 of 47 cases, respectively. The average age at diagnosis was 69 years. All of the tumors were estrogen receptor positive, and the majority expressed progesterone receptor (89 percent), GATA3 (98 percent), FOXA1 (96 percent), and CK8/18 (98 percent). There was an almost equal distribution of luminal A (52 percent) and B (48 percent) carcinomas. Nearly half (49 percent) of the cohort displayed a high risk of recurrence score with the Prosigna test. Patients with a neuroendocrine carcinoma had a shorter disease-free survival compared with those affected by carcinomas of no special type who were matched for age, size, grade, and estrogen-receptor status. No significant differences were observed in terms of overall survival. Stratification of neuroendocrine carcinomas using the 2012 WHO criteria did not reveal statistically significant differences, in terms of progression-free or overall survival, among the categories of well-differentiated neuroendocrine tumors, poorly differentiated neuroendocrine carcinomas, and invasive breast carcinomas with neuroendocrine differentiation. The targeted sequencing analysis found three (seven percent) cases harboring a PIK3CA mutation, and TP53 mutations in three (seven percent) other cases. This study showed that neuroendocrine breast carcinoma is a distinct subtype of luminal carcinoma with a low rate of PIK3CA mutations and aggressive clinical behavior. Accurate identification of neuroendocrine differentiation may be useful to better tailor patient adjuvant therapy within luminal carcinomas.

Lavigne M, Menet E, Tille JC, et al. Comprehensive clinical and molecular analyses of neuroendocrine carcinomas of the breast. Mod Pathol. 2018;31:68–82.

Correspondence: Dr. A. Vincent-Salomon at anne.salomon@curie.fr

 

Role of immune microenvironment in gastrointestinal stromal tumors

The immune microenvironment is a prognostic factor for various malignancies. The significance of key players in the immune microenvironment in gastrointestinal stromal tumors (GISTs), including tumor-infiltrating lymphocytes (TILs) and expression of programmed death-ligand 1 (PD-L1), indoleamine 2,3-dioxygenase (IDO), and tryptophanyl-tRNA synthetase (WARS), is largely unknown. The authors conducted a study in which they constructed tissue microarrays from pathology files dated 1996 to 2016. Immunohistochemistry for PD-L1, IDO, and WARS was correlated with tumor size, mitoses, and outcomes. TILs expressing CD3, CD4, CD8, FoxP3, and GBP5 were counted. The authors analyzed 129 GISTs. The mean patient age was 62.5 years, and 52 percent of patients were male. Tumor location included 89 stomach (69 percent), 33 small bowel (25.6 percent), and seven other (5.4 percent). Mean tumor size was 5.6 cm, and mean mitoses were 7.2 per 50 high-power field. Nineteen (15 percent) patients developed disease progression to the abdominal wall (n = 8), liver (n = 6), or elsewhere (n = 5). Median progression-free survival was 56.6 months; five patients died of disease. PD-L1 was positive in 88 of 127 tumor samples (69 percent); 114 of 127 tumors were IDO positive (89.8 percent); and 60 of 127 tumors were positive for WARS (47.2 percent). PD-L1 was associated with increased size (P = .01), necrosis (P = .018), and mitoses (P = .006). Disease progression was not associated with expression of PD-L1 (P = .44), IDO (P = .14), or WARS (P = .36). PD-L1–positive GISTs with CD8+ or CD3+ TILs were significantly smaller than tumors with CD8+ or CD3+ TILs. The authors concluded that PD-L1 expression was associated with increased size and mitoses. High CD8+ or CD3+ TIL counts were associated with decreased PD-L1/IDO+ GIST size. PD-L1 and IDO could be significant in GIST tumor biology, which invites consideration of immunotherapy as a potential treatment option.

Blakely AM, Matoso A, Patil PA, et al. Role of immune microenvironment in gastrointestinal stromal tumors. Histopathol. 2018;72:405–413.

Correspondence: Dr. L. J. Wang at lwang@lifespan.org

Use of intestinal metaplasia for diagnosis of Barrett esophagus

Barrett esophagus predisposes patients to developing esophageal adenocarcinoma. However, the “global” definition of Barrett esophagus is controversial. Pathologists in most of Europe and the United States require intestinal metaplasia (IM) within columnar-lined mucosa in the tubular esophagus in order to diagnose the condition, whereas pathologists in the United Kingdom and Japan require only the presence of columnar-lined mucosa. To help establish an appropriate definition for Barrett esophagus, the authors evaluated whether IM accompanies esophageal adenocarcinoma, using a U.S. patient cohort. They examined a series of 139 consecutive patients who underwent endoscopic mucosal resections or esophagectomies for esophageal adenocarcinoma at a U.S. tertiary care center. The authors evaluated the resection specimens for the presence (IM+) or absence (IM−) of IM within columnar-lined mucosa. Ninety-seven (70 percent) patients were IM+. Tumors found in IM− patients tended to be advanced at the time of resection (57 percent pT3 or greater, IM−; 31 percent pT3 or greater, IM+; P = .02), such that the tumor may have “overgrown” zones of IM. The authors hypothesized that changes as a result of neoadjuvant chemotherapy or radiation might mask pre-existing IM. When evaluating this hypothesis, they found that 34 of 39 of the treatment-naive patients were IM+. Two of the five IM− patients had prior IM+ biopsies, resulting in 92 percent of treatment-naive patients who were IM+. In the U.S. hospital population, columnar-lined mucosa with IM in the tubular esophagus is found in association with esophageal adenocarcinoma in 70 to 92 percent of patients. The authors concluded that based on these data, the U.S. definition of Barrett esophagus should continue to require the presence of IM.

Salimian KJ, Waters KM, Eze O, et al. Definition of Barrett esophagus in the United States: support for retention of a requirement for goblet cells. Am J Surg Pathol. 2018;​42​(2):​264–268.

Correspondence: Dr. E. A. Montgomery at emontgom@jhmi.edu

Use of select IHC panels in classifying high-grade endometrial carcinomas

Histologic subclassification of high-grade endometrial carcinomas can sometimes be a diagnostic challenge when based on histomorphology alone. The authors conducted a study in which they used immunohistochemical markers to determine the immunophenotype in histologically ambiguous high-grade endometrial carcinomas that were initially diagnosed as pure or mixed high-grade endometrioid carcinoma. The intent of the study was to determine the utility of select immunohistochemical panels for classifying these distinct tumor types, while correlating these findings with clinical outcome. For the study, 43 high-grade endometrial carcinoma cases initially classified as pure high-grade endometrioid carcinoma (n = 32), mixed high-grade endometrioid carcinoma/serous carcinoma (n = 9), and mixed high-grade endometrioid carcinoma/clear cell carcinoma (n = 2) were retrospectively stained with a panel of immunostains, including antibodies for p53, p16, estrogen receptor, and mammaglobin. The authors obtained clinical follow-up data and compared stage-to-stage disease outcomes for different tumor types. Based on aberrant staining for p53 and p16, 17 of 43 (40 percent) of the high-grade endometrial carcinoma cases initially diagnosed as high-grade endometrioid carcinoma were reclassified as serous carcinoma. All 17 cases showed negative staining for mammaglobin, while estrogen receptor was positive in only six (35 percent) cases. The remaining 26 cases of high-grade endometrioid carcinoma showed wild-type staining for p53 in 25 (96 percent) cases and patchy staining for p16 in 20 (77 percent) cases, and they were positive for mammaglobin and estrogen receptor in eight (31 percent) and 19 (73 percent) cases, respectively. This confirmed the initial diagnosis of high-grade endometrioid carcinoma in these cases. In addition, the cases with reclassified serous carcinoma had advanced clinical stages at diagnosis and poorer overall survival on clinical follow-up compared with the remaining 26 high-grade endometrioid carcinoma cases. These results indicate that select immunohistochemical panels, including p53, p16, and mammaglobin, can be helpful in diagnosing cases of histomorphologically ambiguous endometrial carcinomas and can help guide appropriate therapeutic options for such patients.

Hu S, Hinson JL, Matnani R, et al. Are the uterine serous carcinomas underdiagnosed? Histomorphologic and immunohistochemical correlates and clinical follow up in high-grade endometrial carcinomas initially diagnosed as high-grade endometrioid carcinoma. Mod Pathol. 2018;31:358–364.

Correspondence: Dr. R. G. Karabakhtsian at rkarabak@montefiore.org

A clinicopathologic study of aberrant Pax-8 expression in mesothelioma

Serous ovarian neoplasms can overlap morphologically with peritoneal mesothelial proliferations, including well-differentiated papillary mesothelioma and malignant epithelioid mesothelioma. Accurate histologic classification of these neoplasms is important for clinical management. The Pax-8 protein is commonly used for differentiating peritoneal malignant epithelioid mesothelioma (MM) from serous carcinoma, but the diagnostic value of Pax-8 for distinguishing well-differentiated papillary mesothelioma (WDPM) from borderline or low-grade serous tumors is unknown. The authors used immunohistochemical staining to assess Pax-8 expression in 33 WDPMs, 34 peritoneal MMs, 48 pleural MMs, 11 adenomatoid tumors, five peritoneal inclusion cysts, and 51 benign/reactive mesothelium specimens. Staining was noted in 20 (61 percent) WDPMs, with 17 showing strong and diffuse nuclear staining and three patchy/focal staining. Calretinin was expressed in 33 (100 percent) cases, and focal BerEP4 staining was noted in two of 29 (seven percent) cases. In contrast, four (12 percent) peritoneal MMs were Pax-8 positive (three diffuse and one focal staining). All adenomatoid tumors and peritoneal inclusion cysts were negative for Pax-8. Of the 48 pleural MM cases, two (four percent) showed focal weak to moderate nuclear labeling for Pax-8, and two (four percent) cases of reactive mesothelium demonstrated focal and scattered Pax-8 staining. The authors concluded that Pax-8 appears to be a useful marker for distinguishing MM from gynecologic malignancies but is not reliable for distinguishing WDPM from borderline or low-grade gynecologic lesions.