CONTEXT.—: Intestinal neuronal dysplasia type B (IND B) is a complex entity involving the enteric nervous system, clinically manifested with constipation in infancy. Diagnosis has been established by histopathologic analysis of rectal biopsies. However, the criteria for the diagnosis have been questioned and modified, hindering diagnostic practice. OBJECTIVE.—: To analyze the applicability of PTEN immunohistochemistry in the diagnosis of IND B and to compare with control cases and cases of Hirschsprung disease (HD). DESIGN.—: PTEN immunohistochemical expression was analyzed in colorectal samples from 29 cases of IND B and compared with 4 control cases and 6 cases of HD. The pattern of PTEN immunoexpression was analyzed in glial cells of the submucosal and myenteric nerve plexuses and in neural fibrils of the muscularis propria using a scoring system. RESULTS.—: Marked reduction or absence of PTEN expression was observed in glial cells of the submucosal nerve plexuses in all cases of the IND B group and in the myenteric nerve plexuses in 28 of 29 cases (96.5%). Lack of PTEN expression was detected in neural fibrils within the muscularis propria in 21 of 29 cases (72%) of the IND B group. PTEN expression was positive in the same neural structures of the control and HD groups. CONCLUSIONS.—: PTEN immunohistochemistry may be a valuable tool in the diagnostic evaluation of IND B. Lack of or reduction of PTEN expression in neural fibrils within the muscularis propria suggests that involvement of the neuromuscular junction may be a key event in the pathogenesis of the motility disturbance occurring in IND B.

CONTEXT.—: Recent data support that low-risk submucosally invasive (pT1) colonic adenocarcinomas (ie, completely resected tumors that lack high-grade morphology, tumor budding, and lymphovascular invasion) are considered cured via endoscopic resection, provided that the submucosal invasion is less than 1000 μm. Hence, the pathologists' assessment of depth of submucosal invasion may guide further management (ie, surveillance versus colectomy). OBJECTIVE.—: To assess interobserver concordance among gastrointestinal pathologists in measuring submucosal depth of invasion in colonic endoscopic resections. DESIGN.—: Six gastrointestinal pathologists from 5 academic centers independently measured the greatest depth of submucosal invasion in micrometers on 52 hematoxylin-eosin-stained slides from colonic endoscopic specimens with pT1 adenocarcinomas, per published guidelines (round 1 scoring). Two separate measurements (round 2 scoring) were subsequently performed by each pathologist following a consensus meeting, (1) from surface of lesion and (2) from muscularis mucosae, and pathologists were asked to choose their (3) "real-life (best)" assessment between the first 2 measurements. Interobserver agreement was assessed by the intraclass correlation coefficient (ICC) and Cohen κ statistics. RESULTS.—: Round 1 had poor ICC (0.43; 95% CI, 0.31-0.56). Round 2 agreement was good when measuring from surface (ICC = 0.83; 95% CI, 0.76-0.88) but moderate (ICC = 0.59; 95% CI, 0.47- 0.70) when measuring from muscularis mucosae and became poor (ICC = 0.49; 95% CI, 0.36-0.61) for the best-assessment measurement. CONCLUSIONS.—: Our findings indicate that clearer and reproducible guidelines are needed if clinical colleagues are to base important management decisions on pathologists' estimate of depth of submucosal invasion in the colonic endoscopic resections.

CONTEXT.—: Burnout affects 44% of physicians, negatively impacts physicians and the patient care that they provide, and can be assessed by the Maslach Burnout Inventory. Forces contributing to physician burnout have been identified and grouped into 7 dimensions. Burnout within pathology has not been well studied. OBJECTIVE.—: To identify the prevalence of burnout within Canadian pathology, drivers of burnout important in pathology, and pathologist burnout mitigation strategies at an individual and departmental level. DESIGN.—: An electronic survey was disseminated by participating departmental chiefs and the Canadian Association of Pathologists. Survey content included the Maslach Burnout Inventory and 3 free-text questions, including: "What do you find most stressful about your work?" and "What is working for you, at an individual or departmental level, to mitigate against burnout?" Comparative statistics were performed by using Pearson χ2. Significant relationships were sought between pathologist burnout and potential drivers, using Mann-Whitney and Kruskal-Wallis tests. Responses to the qualitative questions were themed and mapped onto the 7 dimensions of burnout. RESULTS.—: Four hundred twenty-seven pathologists participated in the survey from all 10 Canadian provinces. The prevalence of burnout in Canadian pathology was 58% (246 respondents), and there were significant differences by gender and years in practice. Drivers of pathologist burnout included workload and chronic work-related pain. The most frequently reported effective departmental strategy to mitigate against burnout mapped to "organizational culture," and the approach that most individual pathologists have taken to mitigate against burnout involves work-life integration. CONCLUSIONS.—: Burnout within Canadian laboratory medicine is prevalent, and workload is a major driver.

CONTEXT.—: The pathology residency program began in China in 2014. There has been no competency assessment on training programs in the Hubei province of China. OBJECTIVE.—: To evaluate the current residency training curriculum and resident performance in Hubei Province. DESIGN.—: A 37-question online questionnaire was designed to cover general demographic information, diagnostic competency, expectations of ideal caseload for gross and preview, teaching patterns, examinations, research activities, weak points, and other topics in pathology practice. RESULTS.—: A total of 166 participants, including 62 postgraduate year (PGY) 2, 49 PGY3, and 55 new practicing pathologists, responded to the survey. PGY3 residents were found to be more competent than PGY2 in diagnostic competency. Forty-five of 55 new practicing pathologists (81.8%) reported that they could sign out cases independently, whereas 10 of 55 (18.2%) were found to still need transitional time for learning before working independently. Some residents could sign out cytopathology cases and gained knowledge in immunohistochemistry and histochemical staining, while some residents did not receive adequate training in molecular pathology. The ideal caseloads for gross and preview during residency were greater than 5000 and 7000, respectively. Nonneoplastic diseases, neuropathology, dermatopathology, hematopathology, and soft tissue pathology were considered difficult subspecialties in pathology practice. CONCLUSIONS.—: While residents trained in Hubei Province have met the basic requirements for qualified pathologists, more efforts need to be made in many areas, such as well-structured training curriculum and better-designed proficiency examinations. The findings of this study are of great importance to prioritizing training in the future.

CONTEXT.—: Diffuse parenchymal lung disease (DPLD) is a well-recognized complication of systemic connective tissue disease (CTD) but rarely arises in patients with psoriasis or psoriatic arthritis, a poorly understood phenomenon. OBJECTIVE.—: To characterize DPLD associated with psoriasis or psoriatic arthritis, with or without prior immunomodulation. DESIGN.—: Pathology consultation files were searched for patients having psoriasis or psoriatic arthritis and DPLD. After excluding cases with active infection or smoking-related DPLD only, 44 patients (22 women; median age, 60 years; range, 23-81 years) were enrolled. Clinical history and pathology slides were reviewed. RESULTS.—: Twenty-seven of 44 patients (61%) had psoriatic arthritis; the remainder had psoriasis alone. Most presented many years later with nonspecific respiratory symptoms. Nearly one-third had no prior immunosuppression and most had no concomitant CTD. Radiographically, ground-glass opacities, consolidation, and/or reticulation were typical. Histologically, nonspecific interstitial pneumonia and unclassifiable fibrosis were seen in 24 patients (55%) and 8 patients (18%), respectively; usual interstitial pneumonia and airway-centered fibrosis were rare. Superimposed acute lung injury was common, usually manifesting as organizing pneumonia. Lymphoplasmacytic infiltrates, lymphoid aggregates, and chronic pleuritis were frequent. Interstitial granulomas were seen in 17 patients (39%) but were usually rare, poorly formed, and nonnecrotizing. No histologic differences were apparent among patients with or without concomitant CTDs or prior therapy. CONCLUSIONS.—: Some patients with psoriasis or psoriatic arthritis develop clinically significant DPLD, even without prior therapy. Histopathologic findings mirror changes seen with other CTDs. Additional studies are warranted to clarify the association between psoriasis or psoriatic arthritis and DPLD.

CONTEXT.—: Special AT-rich sequence-binding protein 2 (SATB2) induces local chromatin loops to facilitate transcription. SATB2 immunostaining is commonly used as a marker for colorectal adenocarcinoma and osteosarcoma. OBJECTIVE.—: To extend our knowledge on the diagnostic value of SATB2 analysis in a comprehensive set of human tumors. DESIGN.—: Tissue microarrays with 15 012 samples from 120 tumor types and 608 samples of 76 different normal tissues were analyzed. RESULTS.—: SATB2 positivity was found in 89 of 120 different tumor types (74%), including 59 of 120 (49%) with at least 1 moderately positive tumor and 38 of 120 tumor types (32%) with at least 1 strongly positive tumor. Expression was frequent in adenomas (44/42-47/44; 94%-96% positive), adenocarcinomas (1747 of 2023; 86%) and various subtypes of neuroendocrine neoplasms (3/7-12/12; 43%-100%) of the colorectum and appendix, Merkel cell carcinoma (25 of 34, 74%), osteosarcomas (15 of 25; 60%), and papillary renal cell carcinoma (RCC) (121 of 235; 52%). Associations to clinicopathologic tumor features were assessed in colorectal and kidney cancers. In colorectal cancer, weak SATB2 expression was linked to high pT (P < .001), nodal metastasis (P < .001), right-sided tumor location (P < .001), microsatellite instability (P < .001), and BRAF mutations (P = .02). In papillary RCC, low SATB2 expression was associated with high pT (P = .02), distant metastasis (P = .04), and reduced tumor-specific survival (P = .04). In clear cell RCC, low SATB2 expression was linked to high pT (P < .001), high Union for International Cancer Control stage (P < .001), high Thoenes grade (P = .02), and reduced recurrence-free survival (P = .02). CONCLUSIONS.—: Strong SATB2 expression argues for a colorectal origin within adenocarcinomas and neuroendocrine neoplasms. Weak SATB2 expression reflects progression and poor prognosis in colorectal and kidney cancer.

CONTEXT.—: In the late 19th century, mutual autopsy societies formed, first in Paris, France (1876) and later in Philadelphia, Pennsylvania. Members, who were often a who's who of anthropologists, physicians, intellectuals, and highly accomplished citizens, pledged to submit their bodies for autopsies to be performed by living society members so that their brains could be weighed and surface topography studied, with the results to be correlated with the decedents' intelligence and personal strengths during life. OBJECTIVE.—: To explore the short history of these societies, the science they produced, and their extensive newspaper coverage in America. DESIGN.—: Available primary and secondary historic sources were reviewed. RESULTS.—: The Société Mutuelle d'Autopsie in Paris and the American Anthropometric Society in Philadelphia had different motives, as the former was heavily influenced by French Third Republic politics and secularism. The American press provided titillating coverage of both and was particularly fascinated by scandals. In America, Burt Wilder formed a splinter group and established the Wilder Brain Collection at Cornell University. In a period where many anthropologists were making untrue claims that brain and skull measurements were largely determined by race and gender, Wilder and Franklin P. Mall of the Wistar Institute in Philadelphia independently published carefully conducted studies proving this was not the case. CONCLUSIONS.—: Mutual autopsy societies and brain clubs conclusively established that brain weight was not an accurate predictor of intelligence but accomplished little else; they were phased out shortly after World War I but are the predecessor to modern-day brain banks.

CONTEXT.—: Nephrogenic adenoma (NA) is a common urinary tract lesion typically associated with urothelial disruption, leading to implantation of shed renal tubular cells. NA may demonstrate a spectrum of architectural and cytologic features mimicking urothelial carcinoma (UC), adenocarcinoma (including clear cell adenocarcinoma and prostatic adenocarcinoma), and invasion. However, admixed UC and NA has not been described. OBJECTIVE.—: To describe cases where the NA was intimately intermixed with UC, potentially mimicking variant differentiation or invasion. DESIGN.—: In 3 health care systems we identified specimens of NA and UC intimately intermixed with each other where they could mimic a spectrum of one lesion. We assessed patterns of NA and clinical implications of misdiagnosing NA as glandular differentiation of UC. RESULTS.—: There were 4 women and 29 men (median age, 72 years; range, 31-89 years). Twenty-four patients had transurethral resections, 3 had biopsies, and 6 had major resections. Fourteen had noninvasive high-grade papillary UC, 6 had carcinoma in situ, and 11 had invasive high-grade UC, and in 2 patients, NA developed in a papillary urothelial neoplasm with extensive denudation. Three patients had fibromyxoid NA infiltrated by invasive UC. Classical NA (n = 30) had tubulopapillary (n = 18), pure tubular (n = 7), or pure papillary architecture (n = 5). In 1 lesion, NA was present in muscularis propria, and 2 involved adventitia. NA could have been misdiagnosed as invasion in 17 of 22 (77%) noninvasive tumors, or higher stage in 19 of 33 (58%). CONCLUSIONS.—: NA can be intermingled with high-grade UC, expanding the spectrum of entities that must be considered in the differential diagnosis, as it may mimic glandular or tubular differentiation, invasion, and a higher stage of disease. Misinterpretation of NA in such a setting may incorrectly convey a more aggressive biological potential of cancer to clinicians.

CONTEXT.—: Neoadjuvant systemic therapy refers to the use of systemic agent(s) for malignancy prior to surgical treatment and has recently emerged as an option for most breast cancer patients eligible for adjuvant systemic therapy. Consequently, treated breast carcinomas have become routine specimens in pathology practices. A standard protocol has not yet been universally adopted for the evaluation and reporting of these specimens. The American Joint Committee on Cancer staging system recognizes the challenges in staging breast carcinomas after neoadjuvant treatment and provides important data points but does not currently provide detailed guidance in estimating the residual tumor burden in the breast and lymph nodes. The Residual Cancer Burden system is the only Web-based system that quantifies treatment response as a continuous variable using residual tumor burden in the breast and the lymph nodes. OBJECTIVE.—: To provide clarifications and guidance for evaluation and reporting of postneoadjuvant breast specimens, discuss issues with the current staging and reporting systems, and provide specific suggestions for future modifications to the American Joint Committee on Cancer system and the Residual Cancer Burden calculator. DATA SOURCES.—: English-language literature on the subject and the data from the I-SPY 2, a multicenter, adaptive randomization phase 2 neoadjuvant platform trial for early-stage, high-risk breast cancer patients. CONCLUSIONS.—: This article highlights challenges in the pathologic evaluation and reporting of treated breast carcinomas and provides recommendations and clarifications for pathologists and clinicians. It also provides specific recommendations for staging and discusses future directions.

CONTEXT.—: Claudin-18 is expressed in some gastric cancers. Clinical trials are evaluating it as a therapeutic target. OBJECTIVE.—: To evaluate claudin-18 expression in intestinal metaplasia, dysplasia, and adenocarcinoma of distal esophagus/gastroesophageal junction and stomach. To also evaluate claudin-18 expression in gastric and nongastric neuroendocrine tumors as a marker of gastric origin. DESIGN.—: Samples included gastroesophageal junction with intestinal metaplasia (n = 40), dysplasia (n = 54), and adenocarcinoma (n = 20) and stomach with intestinal metaplasia (n = 79), dysplasia (n = 43), and adenocarcinoma (n = 25). Additionally, gastric (n = 40) and nongastric (n = 322) neuroendocrine tumors were included. Claudin-18 expression was evaluated for any staining as positive and by meeting clinical trial inclusion criteria (≥2+ intensity in ≥50% of tumor). RESULTS.—: Claudin-18 staining was not significantly different across dysplasia categories in gastroesophageal junction (P = .11) or stomach (P = .12). Rate of positive staining was higher in gastroesophageal junction than stomach for intestinal metaplasia (37 of 40 [92.5%] versus 37 of 79 [46.8%]; P < .001) and high-grade dysplasia (33 of 38 [86.8%] versus 9 of 16 [56.3%]; P = .03). Intestinal metaplasia showed staining in 7 of 37 autoimmune gastritis samples (18.9%) compared with 30 of 42 without autoimmune gastritis (71.4%) (P < .001). Adenocarcinoma showed similar staining in gastroesophageal junction (15 of 20; 75.0%) and stomach (17 of 25; 68.0%) (P = .85). Eighty percent (32 of 40) of gastric neuroendocrine tumors were positive for claudin-18 expression, with 57.5% (23 of 40) meeting clinical trial inclusion criteria. Comparatively, 0.62% (2 of 322) of nongastric neuroendocrine tumors showed staining (P < .001). CONCLUSIONS.—: Claudin-18 staining was similar in intestinal metaplasia, dysplasia, and adenocarcinoma. Claudin-18 was negative in most cases of intestinal metaplasia in autoimmune gastritis, indicating that intestinal metaplasia in this setting may differ from other forms. Claudin-18 was sensitive and specific for gastric origin in neuroendocrine tumors.

Comment in Arch Pathol Lab Med. 2022 Aug 1;146(8):921-923. Arch Pathol Lab Med. 2022 Aug 1;146(8):924.

Comment in Arch Pathol Lab Med. 2022 Dec 1;146(12):1432.