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.
Analysis of gastrointestinal tract injury from yttrium-90
January 2023—Radioembolization therapy uses yttrium-90-impregnated resin or glass microspheres to selectively target hepatic lesions via transarterial radioembolization. Occasional cases of gastrointestinal (GI) tract injury secondary to nontargeted delivery of microspheres have been reported, but large descriptive pathology series are lacking. The authors conducted a study to assess the pathologic sequelae of biopsy-proven GI injury secondary to yttrium-90 (Y-90) therapy. They also sought to identify differences in the incidence and features of GI injury between resin-based (SIR-Spheres, Sirtex) and glass-based (TheraSphere, Boston Scientific Corp.) Y-90 microspheres. The authors identified 20 cases of histologically confirmed mucosal injury associated with Y-90 from 17 patients and assessed the corresponding clinical and pathologic sequelae. The mucosal biopsies were obtained from one to 88 months after Y-90 therapy (median, five months). Seventeen (85 percent) cases were gastric and the remainder were duodenal. Endoscopic ulceration was seen in 16 (80 percent) cases and mucosal erythema in the remaining four. Nineteen (95 percent) cases showed rounded, dark blue to purple microspheres measuring 4 to 30 μm, consistent with resin microspheres. A single case demonstrated intramucosal translucent glass microspheres measuring 26 µm in diameter. Histologic evidence of ulceration was found in 14 (70 percent) cases, and the microspheres were clearly intravascular in six (30 percent). A foreign body giant cell reaction to the microspheres occurred in only three (15 percent) cases. In a retrospective review of GI tissue obtained postprocedure from 784 sequential patients treated with Y-90 microspheres, three (0.4 percent) patients exhibited resin microspheres upon histologic examination. No cases involving glass-based Y-90 were identified (P=0.0078) despite 630 (80 percent) patients having received glass radioembolization. This increased risk of secondary sphere dissemination is likely related to the increased number of particles required per activity for resin versus glass microspheres. The authors concluded that Y-90 microspheres may be found in the GI tract years after initial liver-targeted therapy and, when present, are often associated with mucosal ulceration. This finding is less likely to be encountered in patients who received Y-90 radioembolization using glass microspheres.
Feely M, Tondon R, Gubbiotti M, et al. Gastrointestinal tract injury by yttrium-90 appears largely restricted to resin microspheres but can occur years after embolization. Am J Surg Pathol. 2022;46:1234–1240.
Correspondence: Dr. Raul S. Gonzalez at rgonzal5@bidmc.harvard.edu
Comparison of Rb1, cyclin D1, and p16 IHC expression for distinguishing SCLC and LCNEC of lung
Large-cell neuroendocrine carcinoma and small cell lung carcinoma are high-grade neuroendocrine tumors and share several fundamental features. Because the tumors may respond to different treatment modalities and show unique molecular alterations, distinguishing between the two is clinically relevant. However, this can be challenging due to sampling and fixation issues and shared morphological features. The authors conducted a study involving surgically resected tumors diagnosed as primary small cell carcinoma (SCLC; n=129) and large-cell neuroendocrine carcinoma (LCNEC; n=27). Tumor sections were immunohistochemically stained with Rb1, cyclin D1, and p16 using tissue microarray. The expression patterns of the proteins were compared between SCLC and LCNEC to identify the discriminatory pattern. All markers had high diagnostic accuracy, with Rb1 being the highest, followed by p16 and cyclin D1. The majority of SCLC had the pattern Rb1-/p16+/cyclin D1-, and more than half of LCNEC had the pattern Rb1+/p16-/cyclin D1+. Overall, the expression pattern Rb1- and cyclin D1- was strongly associated with the diagnosis of SCLC, while the expression pattern Rb1+ and/or cyclin D1+ was strongly associated with LCNEC. P16 did not further discrimination. Use of this simplified expression pattern led to a diagnostic accuracy of 97.3 percent. The heterogeneity of Rb1, cyclin D1, and p16 expression was insignificant in SCLCs compared with LCNECs. The authors concluded that use of Rb1, cyclin D1, and p16 IHC can distinguish between SCLC and LCNEC with a high degree of accuracy. Notably, the Rb1-/cyclin D1- pattern in a given tumor sample would confirm the diagnosis of SCLC. The results could be extrapolated to routine diagnostic samples, such as core biopsies, bronchial biopsies, and cytology samples.
Papaxoinis G, Bille A, McLean E, et al. Comparative study of Rb1, cyclin D1 and p16 immunohistochemistry expression to distinguish lung small-cell carcinoma and large-cell neuroendocrine carcinoma. Histopathology. 2022;81(2):205–214.
Correspondence: Dr. D. Nonaka at dnonaka@msn.com
Assessment of left-sided ulcerative colitis with a cecal/periappendiceal patch of inflammation
Ulcerative colitis is characterized by continuous mucosal inflammation of the rectum, extending uninterrupted to a variable portion of the colon proximally. However, in some patients with distal colitis, a distinct pattern of skip (so-called patch) inflammation involves the cecum or appendiceal orifice, or both. The clinical significance of the proximal patch of inflammation in ulcerative colitis (UC) continues to be debated, and data are limited or contradictory. The authors identified 102 adults who had left-sided UC with a cecal/periappendiceal patch and 102 control subjects who had left-sided UC only. They compared them based on clinicopathologic characteristics and disease outcomes. In multivariate analysis, patients with a patch were younger (median age, 31 versus 41 years; P=0.004) and more likely to have rectosigmoid involvement only (58.8 versus 28.4 percent; P<0.001) compared with patients without a patch. During follow-up, patients with a patch were more likely to eventually be diagnosed with Crohn disease (9.8 versus 1.0 percent; P=0.022) and show proximal extension of inflammation (35.6 versus 10.0 percent; P=0.021). However, they showed no differences in rates of neoplasia, colectomy, or pharmacotherapy escalation compared with the other patient group. Kaplan-Meier analysis confirmed that patients with a biopsy diagnosis of cecal/periappendiceal patch were more likely to show proximal disease extension (P<0.001) and be diagnosed with Crohn disease (P=0.008). The authors concluded that cecal/periappendiceal skip inflammation in left-sided UC occurs more often in younger patients and those with rectosigmoid involvement and is associated with proximal disease extension and, in a small fraction of cases, a change of diagnosis to Crohn disease. However, it does not portend increased risk of neoplasia, pharmacotherapy escalation, or subsequent colectomy in this patient group compared with patients who had left-sided UC only.
Albayrak NE, Polydorides AD. Characteristics and outcomes of left-sided ulcerative colitis with a cecal/periappendiceal patch of inflammation. Am J Surg Pathol. 2022;46:1116–1125.
Correspondence: Dr. Alexandros D. Polydorides at alexandros.polydorides@mountsinai.org
Use of FOXC1 biomarker for triple-negative breast cancer diagnosis and classification
The authors conducted a study to investigate the diagnostic utility of the IHC-based FOXC1 test in breast cancer subtyping and evaluate the correlation between FOXC1 expression and clinicopathologic parameters in triple-negative breast cancer. FOXC1 expression was evaluated using IHC in a cohort of 2,443 breast cancer patients. Receiver operating characteristic (ROC) curves were used to assess the ability of FOXC1 expression to predict the triple-negative phenotype and identify the best cutoff value. FOXC1 expression was correlated with the clinicopathologic parameters of triple-negative breast cancer. The expression rate of FOXC1 in such cancer was significantly higher than in other subtypes. The area under the ROC curve confirmed the high diagnostic value of FOXC1 for predicting the triple-negative phenotype. The cutoff value of one percent showed a maximized sum of sensitivity and specificity. FOXC1 expression was significantly associated with aggressive tumor phenotypes in triple-negative breast cancer. Furthermore, FOXC1 expression was primarily observed in invasive breast carcinoma of no special type and metaplastic carcinoma but rarely in invasive carcinoma with apocrine differentiation. Correspondingly, FOXC1 expression was significantly associated with the expression of basal markers but was negatively correlated with apocrine-related markers in triple-negative breast cancer. The authors concluded that FOXC1 is a highly specific marker for the triple-negative phenotype. Moreover, FOXC1 may serve as an additional diagnostic marker in the histologic and molecular subclassification of triple-negative breast cancer in future studies.
Li M, Lv H, Zhong S, et al. FOXC1: A specific biomarker for triple-negative breast cancer diagnosis and classification. Arch Pathol Lab Med. 2022;146(8):994–1003.
Correspondence: Dr. Wentao Yang at yangwt2000@163.com