CONTEXT.—: Chordomas are uncommon malignant neoplasms with notochordal differentiation encountered by neuropathologists, bone/soft tissue pathologists, and general surgical pathologists. These lesions most commonly arise in the axial skeleton. Optimal therapy typically involves complete surgical resection, which is often technically difficult owing to the anatomic location, leading to a high rate of recurrence. Lesions have been generally resistant to radiation and chemotherapy; however, experimental studies involving targeted therapy and immunotherapy are currently underway. OBJECTIVE.—: To summarize the clinical and pathologic findings of the various types of chordoma (conventional chordoma, dedifferentiated chordoma, and poorly differentiated chordoma), the differential diagnosis, and recent advances in molecular pathogenesis and therapeutic modalities that are reliant on accurate diagnosis. DATA SOURCES.—: Literature review based on PubMed searches containing the term "chordoma" that address novel targeted and immunomodulatory therapeutic modalities; ongoing clinical trials involved in treating chordoma with novel therapeutic modalities identified through the Chordoma Foundation and ClinicalTrials.gov; and the authors' practice experience combined with various authoritative texts concerning the subject. CONCLUSIONS.—: Chordoma is a clinically and histologically unique malignant neoplasm, and numerous diagnostic considerations must be excluded to establish the correct diagnosis. Treatment options have largely been centered on surgical excision with marginal results; however, novel therapeutic options including targeted therapy and immunotherapy are promising means to improve prognosis.

CONTEXT.—: Laboratory managers and medical directors are charged with staffing their clinical laboratories as efficiently as possible. OBJECTIVE.—: To report and analyze the results of 3 College of American Pathologists Q-Probes studies that surveyed the normative rates of laboratory technical staffing ratios. DESIGN.—: Participants in the College of American Pathologists Q-Probes program submitted data on the levels of staffing and test volumes performed in their laboratories in 2014, 2016, and 2019. From these data, we calculated departmental productivity ratios, defined as testing volume per full-time equivalent, and degrees of managerial oversight, defined as the ratio of nonmanagement to management full-time equivalents. Participants completed general questionnaires surveying their hospital and laboratory demographics and practices, the data from which we determined demographic and practice characteristics that were significantly associated with technical staffing ratios. RESULTS.—: Sixty-seven, 82, and 79 institutions submitted data for the years 2019, 2016, and 2014, respectively. Technical staffing ratios varied widely among the various laboratory departments within each institution and among different institutions participating in this study. With the exception of cytology departments, productivity and managerial oversight ratios did not significantly change between these 3 studies. In the 2019 study, greater testing volumes were associated with higher productivity ratios. Significant associations between managerial oversight ratios and practice characteristics were not consistent across the 3 studies. CONCLUSIONS.—: Technical staffing ratios varied widely among the various laboratory departments within each institution and among different institutions participating in this study.

CONTEXT.—: The detection of pancreatic cystic neoplasms (PCNs) has increased owing to the advancement and widespread use of imaging modalities, resulting in differences between past and current management methods for PCNs, including intraductal papillary mucinous neoplasms (IPMNs). Therefore, clinicians should accurately diagnose and determine appropriate treatment strategies. However, previously published treatment guidelines for IPMNs present different indications for treatment. OBJECTIVE.—: To review the current status of PCNs, including epidemiologic change, malignancy risk, and factors for treatment, and to provide the optimal management algorithms for PCNs, including IPMNs, from the clinician's point of view. DATA SOURCES.—: Literature review of published studies and the authors' own work. CONCLUSIONS.—: The treatment of PCNs relies on the type of cyst that is present or suspected. Serous cystic neoplasms are usually benign, and observation is sufficient. However, surgical treatment is required for mucinous cystic neoplasms, and malignancy risk differs according to lesion size. Solid pseudopapillary neoplasms also require surgery. The detection of small IPMNs has been increasing, and most branch duct-type IPMNs are dormant. However, cysts 3 cm or larger or growing branch duct-type IPMNs must be carefully monitored because of the increasing risk of malignancy. Therefore, surveillance strategies should be different according to the size of the lesions. A tailored approach is needed for selecting surgery or surveillance, considering the malignancy potential of the lesion and patient-associated factors such as operative risks and life expectancy. Nomograms are valuable tools for selecting treatment methods as a customized approach for IPMNs.

CONTEXT.—: Pancreatic cystic lesions are increasingly diagnosed. Among other criteria, they are often distinguished in mucinous versus nonmucinous cysts. Mucinous pancreatic cystic lesions have received increasing attention, especially those known as precursors of pancreatic ductal adenocarcinoma. However, the group of nonmucinous cystic lesions of the pancreas includes numerous entities that may pose a diagnostic challenge. Their accurate diagnosis and classification are crucial for adequate patient management. OBJECTIVE.—: To review the spectrum of nonmucinous cystic lesions of the pancreas, taking into consideration their epidemiology and typical clinical context, their characteristic gross morphology and histomorphology, as well as their immunohistochemical and molecular profile. DATA SOURCES.—: Literature was searched and reviewed with MEDLINE via PubMed. Macroscopic and microscopic images were obtained from the archives of the Institute of Pathology, Heinrich Heine University and University Hospital of Duesseldorf, Germany. CONCLUSIONS.—: Nonmucinous cysts of the pancreas comprise numerous, mostly rare entities displaying different biological behaviors. The most frequent are serous cystic neoplasms, solid-pseudopapillary neoplasms, cystic neuroendocrine tumors, and pancreatitis-associated pseudocysts. Accurate diagnosis can be achieved if characteristic clinical context, histomorphology, and immunoprofile are taken into account.

CONTEXT.—: Although most pancreatic and bile duct neoplasms are solid, mucinous cystic neoplasms and intraductal neoplasms have been increasingly recognized even when clinically silent, thanks to the increased use of sensitive imaging techniques. Cystic and intraductal neoplasms of the pancreas are often resectable and curable and constitute about 5% of all pancreatic neoplasms. Owing to their preinvasive nature and different biology, recognition of these entities remains a major priority. Mucinous cystic neoplasms are histologically and clinically distinct from other cystic pancreatic neoplasms. Pancreatic intraductal neoplasms encompass 3 major entities: intraductal papillary mucinous neoplasm, intraductal oncocytic papillary neoplasm, and intraductal tubulopapillary neoplasm. Intraductal papillary neoplasms of bile ducts are also preinvasive mass-forming neoplasms with both similarities and differences with their pancreatic counterparts. All of these pancreatobiliary neoplasms have diverse and distinctive clinicopathologic, genetic, and prognostic variations. OBJECTIVE.—: To review the clinical, pathologic, and molecular features of mucinous cystic and intraductal neoplasms of the pancreatobiliary tract. DATA SOURCES.—: Literature review, diagnostic manuals, and guidelines. CONCLUSIONS.—: This review will briefly describe well-known clinical and pathologic features and will focus on selected recently described aspects of morphology, grading, classification, and genomic alterations of cystic and intraductal neoplasms of the pancreatobiliary tract.

Comment in Arch Pathol Lab Med. 2021 Oct 1;145(10):1193b-1193.

CONTEXT.—: Metaplastic breast carcinoma is an aggressive form of breast cancer that accounts for 0.5% to 3% of all breast cancers. OBJECTIVE.—: To study the clinicopathologic characteristics and outcomes of this rare disease. DESIGN.—: Retrospective study of patients with a diagnosis of metaplastic breast carcinoma between 2000 and 2019. Hematoxylin-eosin-stained slides were reviewed and additional clinical data were obtained from electronic medical records. Univariable and multivariable Cox proportional hazard regression analyses were used to determine associations between overall survival and several clinicopathologic variables. RESULTS.—: Of the 125 patients with metaplastic breast carcinoma identified, only patients with high-grade disease (N = 115) were included in the data analysis. A total of 38 participants (33%) were white, 66 (57%) were African American, and 11 (10%) belonged to other ethnicities. The median age at diagnosis was 57 years. The median tumor size was 3 cm. Heterologous histology was seen in 30% of cases. Multivariable analyses showed that patients with a larger tumor size had worse overall survival (hazard ratio [HR], 1.25; 95% CI, 1.10-1.44; P < .001). Distant metastatic disease was also associated with worse overall survival on multivariable analysis (HR, 10.27; 95% CI, 2.03-55.54; P = .005). In addition to treatment with either partial or complete mastectomies, 84 patients (73%) received chemotherapy. Multivariable analyses showed that chemotherapy had no effect on overall survival (HR, 0.53; 95% CI, 0.09-6.05; P = .55). CONCLUSIONS.—: A larger tumor size and distant metastatic disease are associated with worse overall survival in patients with metaplastic breast carcinoma. Additional studies are needed to further characterize our findings.

CONTEXT.—: RET gene fusions are oncogenic drivers in nonsmall cell lung cancer and nonmedullary thyroid cancer. Selpercatinib (RETEVMO), a targeted inhibitor of RET, was approved by the US Food and Drug Administration for the treatment of RET fusion-positive nonsmall cell lung cancer and nonmedullary thyroid cancer emphasizing the need for rapid and accurate diagnosis of RET fusions. Fluorescence in situ hybridization (FISH) has been used to detect gene rearrangements, but its performance detecting RET rearrangements is understudied. OBJECTIVE.—: To validate and describe the performance of Abbott Molecular RET break-apart FISH probes for detecting RET rearrangements. DESIGN.—: A training set with RET fusion-positive (13) and RET fusion-negative nonsmall cell lung cancer and nonmedullary thyroid cancer samples (12) was used to establish criteria for FISH scoring. The scoring criteria was then applied to a larger validation set of samples (96). RESULTS.—: A cutoff of 19% or more positive nuclei by FISH was established in the training set and determined by the mean ±3 SD. The validation set was tested using Abbott Molecular RET break-apart FISH compared with sequencing. With this cutoff, a sensitivity of 86% (12 of 14) and specificity of 99% (81 of 82) was achieved. Bootstrapping showed sensitivity could be optimized by using a greater than 13% cutoff with indeterminate samples of 13% to 18% abnormal nuclei requiring confirmation by an orthogonal method. Using this 3-tier scoring system sensitivity increased to 100% (14 of 14) and specificity was 96% (79 of 82). CONCLUSIONS.—: Abbott Molecular break-apart FISH probes can be used to detect RET fusions. Laboratories can optimize cutoffs and/or testing algorithms to maximize sensitivity and specificity to ensure appropriate patients receive effective, timely therapy.

CONTEXT.—: Clinical laboratory processes that require cooperation among geographically distinct sections often face challenges. We describe these challenges as related to the Gram staining of cerebrospinal fluid, a key test in the management of patients with suspected central nervous system infections, and our attempts to improve quality outcomes. OBJECTIVE.—: To evaluate multiple tools and strategies for their effectiveness in optimizing the turnaround time of tests sharing a specimen or workflow. DESIGN.—: Over the course of 5 years, the turnaround time of cerebrospinal fluid Gram stain was studied at one of the largest children's health systems in the United States. Baseline data showed suboptimal compliance to targeted turnaround times. A conventional approach to process standardization and 2 innovative tools that facilitate horizontal integration were applied to the main campus laboratory as follows: a daily operational huddle and a novel electronic communication application that was interfaced with the laboratory information system. Turnaround time and its variation were assessed. Two other hospital laboratories within the health system that did not undergo these quality interventions served as controls. RESULTS.—: Standardization of processes reduced the variability of turnaround time but only minimally shortened it. In contrast, an interteam daily huddle that monitored key quality metrics together with the communication application improved turnaround time significantly and sustainably. CONCLUSIONS.—: Communication strategies involving a physical or virtual gathering of laboratory representatives encourage horizontal communication and improve turnaround times. These tools are generally applicable and could be used to improve other processes in healthcare, especially those where a workflow is shared between 2 geographically distinct areas of a health system.

CONTEXT.—: Placental pathology is an essential tool for understanding neonatal illness. The recent Amsterdam international consensus has standardized criteria and terminology, providing harmonized data for research and clinical care. OBJECTIVE.—: To evaluate the interobserver reliability of these criteria between pathologists at different levels of experience using digitally scanned slides from placentas in a birth population including a large proportion of normal deliveries. DESIGN.—: This was a secondary analysis of selected placentas from a large case-control study of placental lesions associated with neonatal encephalopathy. Histologic slides from 80 placentas were digitally scanned and blindly evaluated by 6 pathologists. Interobserver reliability was assessed by positive and negative agreement, Fleiss κ, and interrater correlation coefficients. RESULTS.—: Overall agreement on the diagnosis, grading, and staging of acute chorioamnionitis and villitis of unknown etiology was moderate to good for all observers and good to excellent for a subset of 4 observers. Agreement on the diagnosis and subtyping of fetal vascular malperfusion was poor to fair for all observers and fair to moderate for the subset of 4 pathologists. Agreement on accelerated villous maturation was poor. CONCLUSIONS.—: This study critically evaluates interobserver reliability for lesions defined by the Amsterdam consensus using scanned images with a low frequency of pathologic lesions. Although reliability was good to excellent for inflammatory lesions, lower reliability for vascular lesions emphasizes the need to more explicitly define the specific histologic features and boundaries for these patterns.

CONTEXT.—: The gold standard test to identify the presence of SARS-CoV-2 in COVID-19 patients is the real-time reverse transcription-quantitative polymerase chain reaction (RT-qPCR), but inconclusive data and false-positive diagnosis remain the major problem of this approach. OBJECTIVE.—: To compare the fitness of 2 primer sets to the SARS-CoV-2 nucleocapsid phosphoprotein gene (NP) in the molecular diagnosis of COVID-19, we verified the inconclusive data and confidence of high cycle threshold (Ct) values in SARS-CoV-2 detection. DESIGN.—: The 970 patient samples were tested by using United States Centers for Disease Control and Prevention protocol. We compared the fitness of 2 primer sets to 2 different regions of the NP gene. In addition, we checked the consistency of positive samples with high Ct values by retesting extracted SARS-CoV-2 RNA or by second testing of patients. RESULTS.—: N1 and N2 displayed similar fitness during testing, with no differences between Ct values. Then, we verified security range Ct values related to positive diagnostics, with Ct values above 34 failing in 21 of 32 cases (65.6%) after retesting of samples. The patient samples with Ct values above 34.89 that were doubly positive revealed a low sensitivity (52.4%) and specificity (63.6%) of the test in samples with Ct values above 34. CONCLUSIONS.—: It is safe to use 1 primer set for the NP gene to identify SARS-CoV-2 in samples. However, samples with high Ct values may be considered inconclusive and retested to avoid false-positive diagnosis.

CONTEXT.—: Hypergastrinemia states such as achlorhydria from gastric mucosal atrophy or a gastrin-producing tumor in humans have been associated with the development of enterochromaffin-like (ECL) cell hyperplasia and gastric neuroendocrine tumors (GNETs). Whether drugs that can elevate serum gastrin levels, such as proton pump inhibitors (PPIs), can produce the same tissue effect is not known, and there is no concrete evidence linking the use of PPIs to GNETs outside animal models and case reports. OBJECTIVE.—: To explore the clinicopathologic association for GNETs of presumed ECL cell origin that cannot be reliably placed into any of the 3 established categories currently recognized by the World Health Organization. DESIGN.—: This is a retrospective clinicopathologic study of GNETs in the body/fundus during a period of 15 years (2005-2019). RESULTS.—: Of a total of 87 cases, 57 (65.5%) were associated with atrophic gastritis, 2 (2.3%) were associated with Zollinger-Ellison syndrome, and 28 (32.2%) were unclassified. Of the latter, 11 were consistent with true sporadic/type 3 GNETs, while 17 had background mucosal changes of parietal cell and ECL cell hyperplasia but without underlying detectable gastrinoma, and 88.2% (15 of 17) of patients from this group had documented long-term PPI use. This subtype of GNETs was more commonly multifocal and of higher grade (P = .03) than "true" sporadic GNETs. CONCLUSIONS.—: A subset of GNETs arises in the background of gastric mucosal changes suggestive of hypergastrinemia, but without underlying gastrinoma, and could be linked to long-term PPI use.