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, associate pathologist, Brigham and Women’s Hospital, Boston; and Amarpreet Bhalla, MD, assistant professor of pathology, Albert Einstein College of Medicine, Montefiore Medical Center.
Effectiveness of deficient mismatch repair screening of advanced adenomas in population screening for CRC
October 2024—Screening for colorectal cancers can involve assessing mismatch repair deficiency or microsatellite instability to identify people with Lynch syndrome, the most common hereditary syndrome causing colorectal cancer. Advanced adenomas are considered immediate precursor lesions of colorectal cancer. The authors conducted a study in which they investigated the relevance of microsatellite instability screening of advanced adenomas for Lynch syndrome in population screening. They selected advanced adenomas (n=1,572) from the Dutch colorectal cancer population screening program. All were reviewed and met one or more of the following criteria: tubulovillous (n=848, 54 percent) or villous (n=118, 7.5 percent) adenoma, diameter of 1 cm or more (n=1,286, 82 percent), or high-grade dysplasia (n=176, 11 percent). All three criteria were fulfilled simultaneously in 86 (five percent) cases. Mismatch repair-IHC or microsatellite instability analyses, or both, were performed on all cases. Only five (0.3 percent) advanced adenomas showed mismatch repair deficiency and microsatellite instability, including two cases with hypermethylation. A germline event was suspected in at least two patients based on allelic frequencies. No pathogenic explanation was found in the last case. The authors concluded that timely testing of precursor lesions is preferable to detect new Lynch syndrome patients before they develop colorectal cancer. Standard assessment of mismatch repair deficiency to uncover Lynch syndrome patients by screening advanced adenomas from the population screening is not effective.
Vink-Börger E, Dabir PD, Krekels J, et al. Deficient mismatch repair screening of advanced adenomas in the population screening program for colorectal cancer is not effective. Histopathology. 2024;84(6):1056–1060.
Correspondence: Dr. Iris D. Nagtegaal at nagtegaal@radboudumc.nl
Distinguishing BRAF-mutated and morphologically spitzoid tumors from true Spitz neoplasms
Drivers of Spitz neoplasms include activating point mutations in HRAS and Spitz-associated genomic fusions. Some BRAF-mutated melanocytic neoplasms can morphologically mimic Spitz tumors (STs). These have been termed BRAF-mutated and morphologically spitzoid (BAMS). The authors conducted a study to determine whether expert pathologists from the International Melanoma Pathology Study Group could distinguish between BAMS nevi or tumors and true STs with Spitz-associated genomic fusions or an HRAS mutation. Seventeen experts in melanoma pathology from the study group assessed 54 cases—40 BAMS and 14 true STs. They reviewed the cases blinded to the genomic data and selected among several diagnostic options, including BAMS, ST, melanoma, and “other.” The experts’ blinded assessment of the BAMS group generated nearly equal numbers of diagnostic selections for BAMS (38 percent) and ST (32 percent). The favored diagnosis was BAMS in 22 of the BAMS cases and ST in 17. Ten of the 20 cases in the group of 54 with the highest number of votes for ST were BAMS. More than 75 percent of BAMS cases had enough votes for ST that they fell within the standard deviation of votes for ST seen among true ST cases. Poor interobserver agreement was noted for the precise diagnosis of BAMS (κ=0.16), but there was good agreement that these cases were not melanoma (κ=0.7). The authors concluded that BAMS nevi and tumors can closely mimic Spitz neoplasms. The pathologists in this study favored a diagnosis of ST in nearly half of BAMS cases. Even the experts cannot morphologically distinguish some BAMS from true Spitz neoplasms.
Gerami P, Chen A, Sharma N, et al. BRAF mutated and morphologically spitzoid tumors, a subgroup of melanocytic neoplasms difficult to distinguish from true Spitz neoplasms. Am J Surg Pathol. 2024;48(5):538–545.
Correspondence: Dr. Pedram Gerami at pedram.gerami@nm.org
Genetic landscape of pediatric acute liver failure of indeterminate origin
Pediatric acute liver failure is a life-threatening condition. In Europe, the main causes are viral infections (12 to 16 percent) and inherited metabolic diseases (14 to 28 percent). Yet the underlying etiology remains elusive in up to 50 percent of cases, challenging clinical management, including the use of liver transplantation. The authors conducted an international, multicenter study in which they systematically analyzed indeterminate cases of pediatric acute liver failure (PALF) referred for genetic evaluation that used whole exome sequencing (WES). They studied phenotypic and biochemical markers and the diagnostic yield of WES in this condition in patients younger than one to 18 years old. A total of 260 patients with indeterminate PALF from 19 countries were recruited for the study between 2011 and 2022, of whom 59 had recurrent PALF. WES established a genetic diagnosis in 37 percent (97 of 260) of cases. Diagnostic yield was highest in children with PALF during the first year of life (41 percent) and in children with recurrent acute liver failure (64 percent). Thirty-six distinct disease genes were identified. Defects in NBAS (n=20), MPV17 (n=8), and DGUOK (n=7) were the most frequent findings. When categorizing the disease genes into functional groups, most cases were associated with mitochondrial diseases (45 percent), disorders of vesicular trafficking (28 percent), and cytosolic aminoacyl-tRNA synthetase deficiencies (10 percent). One-third of patients had a fatal outcome. Fifty-six patients underwent liver transplantation. The authors concluded that their study demonstrates that WES can help diagnose a relevant number of cases of indeterminate PALF. Therefore, WES, and in the near future whole genome sequencing, should be part of a first-line diagnostic approach for children presenting with PALF.
Lenz D, Schlieben LD, Shimura M, et al. Genetic landscape of pediatric acute liver failure of indeterminate origin. Hepatology. 2024;79(5):1075–1087.
Correspondence: Dr. Christian Staufner at christian.staufner@med.uni-heidelberg.de or Dr. Holger Prokisch at holger.prokisch@helmholtz-munich.de
Outcome-based risk stratification model for diagnosing placental maternal vascular malperfusion
The Amsterdam Consensus Statement introduced the term maternal vascular malperfusion as a means to group a constellation of findings associated with impaired maternal-placental circulation. In isolation, these findings are relatively common in placentas from normal gestations. The consensus statement did not enumerate which findings, how many, and to what extent findings must be present to establish a diagnosis of maternal vascular malperfusion (MVM). The authors conducted a study to determine the criteria essential for correlating MVM diagnosis with obstetrical outcomes. A total of 200 placentas (100 with a reported diagnosis of MVM and 100 controls matched by maternal age and gravida-para-abortus status) were reviewed to document features of MVM. Obstetrical outcomes in the current pregnancy were recorded. Those included hypertension, pre-eclampsia with or without severe features, gestational diabetes, premature birth, fetal growth restriction, and intrauterine fetal demise. On univariate logistic regression analysis, adverse outcome was associated with low placental weight (less than the 10th percentile for gestational age), accelerated villous maturation, decidual arteriopathy, infarcts (presence and volume), distal villous hypoplasia, and excess multinucleated trophoblast of at least 2 mm in the basal plate (all P<.01) but not with retroplacental hemorrhage. In a multivariable model, decidual arteriopathy, infarcts, and accelerated villous maturation were significantly associated with adverse outcomes, while low placental weight showed a trend toward significance. A receiver-operating characteristic curve that included these four parameters showed good predictive ability (area under the curve, 0.8256). Based on the probability of an adverse outcome, the authors recommend consistent reporting of decidual arteriopathy, accelerated villous maturation, infarcts, and low placental weight, grouping them as “diagnostic of MVM” (if there is decidual arteriopathy or accelerated villous maturation plus any other feature, yielding a probability of 65 to 97 percent for adverse obstetrical outcomes) or “suggestive of MVM” (if only one feature is present or if placental infarction and low placental weight are the only two features, yielding a probability of up to 52 percent). Other features, such as distal villous hypoplasia, excess multinucleated trophoblast (2 mm or greater), and retroplacental hemorrhage, can also be reported, but their role in MVM diagnosis should be studied further.
Davis DL, Lechner AC, Chapel DB, et al. Outcome-based risk stratification model for the diagnosis of placental maternal vascular malperfusion. Mod Pathol. 2024;37. doi:10.1016/j.modpat.2023.100370
Correspondence: Dr. Carlos Parra-Herran at cparra-herran@bwh.harvard.edu