Context.—:In 2016, the College of American Pathologists published an evidence-based guideline to develop recommendations for interpretive diagnostic error reduction in anatomic pathology. New evidence, together with evolving practice environments and the continued adoption of digital technologies, including artificial intelligence, has prompted a review of the guideline. Objective.—:To assess evidence published since the release of the original guideline and update evidence-based recommendations for the reduction of diagnostic errors. Design.—:The College of American Pathologists, in collaboration with the Association of Directors of Anatomic and Subspecialty Pathology, convened a panel of experts to update the 2016 evidence-based guideline. A systematic literature review was conducted to address 4 key questions. Using the Grading of Recommendations Assessment, Development and Evaluation approach, recommendations were created based on the available evidence, certainty of that evidence, and key judgments as defined in the Grading of Recommendations Assessment, Development and Evaluation framework. Results.—:Two strong recommendations and 4 good practice statements were established for the reduction of diagnostic error. Conclusions.—:The expert panel recommends that anatomic pathologists implement procedures for the review of pathology cases to detect and correct potential interpretive errors to improve patient outcomes.

Pilomatrix-like high-grade endometrial carcinoma (PiMHEC) is a rare and aggressive variant of endometrial carcinoma often misdiagnosed due to overlapping features with other high-grade malignancies. This study characterizes its clinicopathologic, immunophenotypic, and molecular features to establish key diagnostic criteria and propose a standardized terminology. Ten tumors were analyzed using histopathologic examination, immunohistochemistry, and next-generation sequencing. All but 1 tumor exhibited both low-grade endometrioid and high-grade basaloid components, the latter characterized by either geographic or comedo-type necrosis and shadow cells. Although shadow cells are a hallmark feature, they may be focal or absent, necessitating careful evaluation. High-grade areas consistently showed ER and PR negativity with diffuse nuclear β-catenin staining, correlating with CTNNB1 exon 3 mutations in all tumors. Identical CTNNB1 mutations in spatially distinct tumor components suggest a clonal progression from a low-grade precursor. Additional mutations in ARID1A, PTEN, and PIK3CA were identified. Clinically, PiMHEC exhibited aggressive behavior, with 7 patients experiencing recurrence and 1 succumbing to the disease within 9 months. Metastatic sites included the lungs, liver, lymph nodes, and abdominal wall. PD-L1 expression in 4 tumors suggests potential responsiveness to immune checkpoint inhibitors, whereas low-level HER2 expression (1+ to 2+) in 5 tumors raises the possibility of HER2-targeted therapies. Folate receptor alpha was not expressed in any tumor. In conclusion, PiMHEC is a distinct and highly aggressive endometrial carcinoma with unique histopathologic and molecular features that differentiate it from high-grade endometrioid and other high-grade endometrial cancers including squamous cell carcinoma in rare situations. Its key diagnostic features include high-grade basaloid tumor cells associated with shadow cells, tumor necrosis, and diffuse nuclear β-catenin staining. To improve diagnostic accuracy and reduce ambiguity, we propose adopting “pilomatrix-like high-grade endometrial carcinoma” as a standardized term.

Mucinous neoplasms associated with ovarian teratomas (MOvNTs) are uncommon with only a few large series published thus far. Their clinicopathologic features are evaluated in this multi-institutional study. Fifty MOvNTs were retrieved from the files of four institutions over 16-years (yr). Patient age, CEA and CA-125 levels, laterality, tumor size, type of mucinous tumor (according to gynecologic pathology criteria and proposed appendiceal nomenclature when applicable), immunohistochemistry (IHC), FIGO stage, presence of pseudomyxoma ovarii and peritonei, treatment, follow-up in months (mos), and outcome were recorded. Patients ranged in age from 17 years to 74 years (mean 43, median, 42). Increased CA-125 levels correlated with mucinous carcinoma and mucinous borderline tumor (p=0.0270), and CEA correlated with mucinous carcinoma (p=0.0256). Mucinous neoplasms were either cystadenomas (16), borderline tumors (20) or carcinomas (14). Forty-one were Mullerian/surface epithelial type and 9 were appendiceal-like. Using appendiceal nomenclature: Seven were low grade mucinous appendiceal neoplasms and 2 high grade appendiceal neoplasms. IHC: 39 % were CK20/CDX2/SATB2 positive and 61 % were CK7 > CK20 (+), and SATB2-. Almost all patients presented with FIGO stage I disease; except one each with FIGO II and IIIC disease. All patients had surgical resection, and 10 patients had adjuvant therapy. Recurrences occurred in 4 patients (range: 10-84 mos). At last follow-up (median 60 mos): 33 patients had no evidence of disease, 3 died of disease, 1 was alive with disease, 2 died of other causes, and 11 were lost to follow-up. MOvNTs are usually Mullerian/surface epithelial type and FIGO stage I. As the only patients with adverse outcome were those who had a diagnosis of mucinous carcinoma or microinvasive carcinoma, whether of appendiceal-like or Mullerian/surface epithelial type, using established gynecologic, rather than GI criteria for classifying all types of MOvNTs is recommended.

Context.— The subspecialty workforce in pathology globally is inadequate for the demands of many modern therapies. The Open Pathology Education Network (OPEN) was formed to augment the global pathology workforce. The International Gynecologic Cancer Society (IGCS) virtual gynecologic-oncology (gyn-onc) fellowship training identified needs for higher-level pathology support. Objective.— To report on an OPEN-IGCS pilot project to support gyn-onc and pathology education efforts in a developing country. Design.— Curriculum with learning objectives and content from open sources was assembled. Mentoring sessions included bidirectional case sharing. Trainees received sequential curricula assignments and had options for communication outside mentoring sessions. Pretest and posttest digital slide assessments were included. Mentors attended the gynecology tumor board, allowing for the assessment of quality and accuracy of pathology diagnosis for cases discussed. Results.— Learners completing the pretest and posttest showed substantial improvement, with 2 practicing pathologists improving their diagnostic scores from 60% to an average of 95%. A third trainee-level participant also improved, but to a lesser degree. Qualitative assessments included increased confidence in presentation and an increased ability to anticipate questions, raise issues of expanded differential diagnoses, and articulate appropriate workup. Observations of clinicians who participated also noted increased confidence in participating pathologists. Secondary value included establishing an expanded network of support in other subspecialties for participants. Pathologic issues at the tumor board decreased, from more than 50% in the first 3 months of study to 0% in the last 3 months of study. The curriculum was embedded into a self-paced learning portal at courses.open-pathology.org. Conclusions.— The OPEN-IGCS collaboration model shows the potential to provide subspecialty pathology training remotely.

Pilomatrix-like high-grade endometrial carcinoma (PiMHEC) is a rare and aggressive variant of endometrial carcinoma often misdiagnosed due to overlapping features with other high-grade malignancies. This study characterizes its clinicopathologic, immunophenotypic, and molecular features to establish key diagnostic criteria and propose a standardized terminology. Ten tumors were analyzed using histopathologic examination, immunohistochemistry, and next-generation sequencing. All but 1 tumor exhibited both low-grade endometrioid and high-grade basaloid components, the latter characterized by either geographic or comedo-type necrosis and shadow cells. Although shadow cells are a hallmark feature, they may be focal or absent, necessitating careful evaluation. High-grade areas consistently showed ER and PR negativity with diffuse nuclear β-catenin staining, correlating with CTNNB1 exon 3 mutations in all tumors. Identical CTNNB1 mutations in spatially distinct tumor components suggest a clonal progression from a low-grade precursor. Additional mutations in ARID1A, PTEN, and PIK3CA were identified. Clinically, PiMHEC exhibited aggressive behavior, with 7 patients experiencing recurrence and 1 succumbing to the disease within 9 months. Metastatic sites included the lungs, liver, lymph nodes, and abdominal wall. PD-L1 expression in 4 tumors suggests potential responsiveness to immune checkpoint inhibitors, whereas low-level HER2 expression (1+ to 2+) in 5 tumors raises the possibility of HER2-targeted therapies. Folate receptor alpha was not expressed in any tumor. In conclusion, PiMHEC is a distinct and highly aggressive endometrial carcinoma with unique histopathologic and molecular features that differentiate it from high-grade endometrioid and other high-grade endometrial cancers including squamous cell carcinoma in rare situations. Its key diagnostic features include high-grade basaloid tumor cells associated with shadow cells, tumor necrosis, and diffuse nuclear β-catenin staining. To improve diagnostic accuracy and reduce ambiguity, we propose adopting "pilomatrix-like high-grade endometrial carcinoma" as a standardized term.

Steroid cell tumors (SCTs) of the ovary are rare and understudied, and as such, uncertainties remain about their malignant potential, as well as clinicopathologic predictors of patient outcome. Based on a multi-institutional cohort of cases, we present findings from the largest study of SCT reported to date. Clinicopathologic data were documented on 115 cases of SCT that were assembled from 17 institutions. The median patient age was 55 years (range: 9 to 84). When measured, preoperative androgen levels were elevated in 84.2% (48/57) of patients. A total of 111 (96.5%) cases were classified as stage I (103 stage IA; 2 stage IB; 6 stage IC). The stage distribution for the remaining 4 patients was as follows: stage II (n = 1), III (n = 3; 1 IIIA, 1 IIIB, 1 IIIC). The median tumor size was 3 cm (range: 0.2 to 22). Cytologic atypia, microscopic tumor necrosis, microscopic tumor hemorrhage, and a mitotic index of >1 mitotic figure/10 high-power fields were present in 52% (60/115), 9.6% (11/115), 37% (43/115), and 19% (22/115) of cases, respectively. Of 115 patients, 7 (6.1%) recurred postexcision, 4 (3.5%) ultimately died of disease, and 10 (8.7%) either recurred, died of disease, or were advanced stage at presentation. The median duration to recurrence postresection was 33 months (range: 23 to 180). Four of the 7 recurrences were stage IA at baseline. Tumor size >4 cm, International Federation of Gynecology and Obstetrics (FIGO) stage >= IB, tumor necrosis, and tumor hemorrhage were each significantly associated with reduced recurrence-free survival in log-rank tests and univariable Cox models, with age older than 65 years being of marginal significance (hazard ratio [HR]: 5.4, 95% CI: 1.0-30.0, P = 0.05). Multivariable analyses suggested that FIGO stage >= IB (HR: 27.5, 95% CI: 2.6-290.5), and age older than > 65 years (HR: 21.8, 95% CI: 1.6-303.9) were the only parameters that were independently associated with recurrence. Cross-section analyses showed that tumor necrosis, tumor hemorrhage, and larger tumor size were significantly associated with a FIGO stage >= IB status, which bolstered the conclusion that they are not independent predictors of recurrence. In summary, < 10% of SCTs are clinically malignant, a substantially lower frequency than has previously been reported in the literature. Clinicopathologic predictors of patient outcomes that are prospectively applicable in practice could not be definitively established. Recurrences may occur many years (up to 15 y in this study) after primary resection, even in stage IA cases.

Steroid cell tumors (SCTs) of the ovary are rare and understudied, and as such, uncertainties remain about their malignant potential, as well as clinicopathologic predictors of patient outcome. Based on a multi-institutional cohort of cases, we present findings from the largest study of SCT reported to date. Clinicopathologic data were documented on 115 cases of SCT that were assembled from 17 institutions. The median patient age was 55 years (range: 9 to 84). When measured, preoperative androgen levels were elevated in 84.2% (48/57) of patients. A total of 111 (96.5%) cases were classified as stage I (103 stage IA; 2 stage IB; 6 stage IC). The stage distribution for the remaining 4 patients was as follows: stage II (n = 1), III (n = 3; 1 IIIA, 1 IIIB, 1 IIIC). The median tumor size was 3 cm (range: 0.2 to 22). Cytologic atypia, microscopic tumor necrosis, microscopic tumor hemorrhage, and a mitotic index of >1 mitotic figure/10 high-power fields were present in 52% (60/115), 9.6% (11/115), 37% (43/115), and 19% (22/115) of cases, respectively. Of 115 patients, 7 (6.1%) recurred postexcision, 4 (3.5%) ultimately died of disease, and 10 (8.7%) either recurred, died of disease, or were advanced stage at presentation. The median duration to recurrence postresection was 33 months (range: 23 to 180). Four of the 7 recurrences were stage IA at baseline. Tumor size >4 cm, International Federation of Gynecology and Obstetrics (FIGO) stage ≥IB, tumor necrosis, and tumor hemorrhage were each significantly associated with reduced recurrence-free survival in log-rank tests and univariable Cox models, with age older than 65 years being of marginal significance (hazard ratio [HR]: 5.4, 95% CI: 1.0-30.0, P = 0.05). Multivariable analyses suggested that FIGO stage ≥IB (HR: 27.5, 95% CI: 2.6-290.5), and age older than >65 years (HR: 21.8, 95% CI: 1.6-303.9) were the only parameters that were independently associated with recurrence. Cross-section analyses showed that tumor necrosis, tumor hemorrhage, and larger tumor size were significantly associated with a FIGO stage ≥IB status, which bolstered the conclusion that they are not independent predictors of recurrence. In summary, <10% of SCTs are clinically malignant, a substantially lower frequency than has previously been reported in the literature. Clinicopathologic predictors of patient outcomes that are prospectively applicable in practice could not be definitively established. Recurrences may occur many years (up to 15 y in this study) after primary resection, even in stage IA cases.

Endometriosis is often diagnosed in reproductive aged women with spontaneous ovarian activity. Here we described a case of endometriosis diagnosed in a patient with premature ovarian insufficiency (POI) due to prepubertal bone marrow transplant (BMT). The patient is a 22-year-old nulligravid female who presented with chronic pelvic pain. She had an inherited bone marrow failure syndrome (Diamond-Blackfan anemia), which required gonadotoxic chemotherapy for BMT at a young age prior to puberty. At age 13, she received hormone therapy with transdermal estrogen with subsequent addition of cyclic progestin and was later transitioned to combined oral contraceptive pills (COC). Endometriosis was suspected due to progressive dysmenorrhea and multiple cyclic systemic symptoms. She underwent a trial of elagolix, but could not tolerate it due to worsened arthralgia. Norethindrone acetate (NET-A) was then started, and she underwent diagnostic laparoscopy. Laparoscopy revealed scattered superficial endometriotic lesions in the pelvis. Histological studies showed florid endometriosis. Patient continues on NET-A 10mg and oral estradiol 0.5mg daily since the surgery and has experienced sustained improvement in her symptoms. Endometriosis should be considered as a possible cause for progressive dysmenorrhea or pelvic pain, even in the setting of POI. The balance between HT for overall health benefits in young women with POI and the risk of endometriosis exacerbation is delicate, but achievable.

Background Adverse medical events affect 10% of American households annually, inducing a variety of harms and attitudinal changes. The impact of adverse events on perceived abandonment by patients and their care partners has not been methodically assessed.Objective To identify ways in which providers, patients and families responded to medical mishaps, linking these qualitatively and statistically to reported feelings of abandonment and sequelae induced by perceived abandonment.Methods Mixed-methods analysis of responses to the Massachusetts Medical Errors Recontact survey with participants reporting a medical error within the past 5 years. The survey consisted of forty closed and open-ended questions examining adverse medical events and their consequences. Respondents were asked whether they felt ‘that the doctors abandoned or betrayed you or your family’. Open-ended responses were analysed with a coding schema by two clinician coders.Results Of the 253 respondents, 34.5% initially and 20% persistently experienced abandonment. Perceived abandonment could be traced to interactions before (18%), during (34%) and after (45%) the medical mishap. Comprehensive post-incident communication reduced abandonment for patients staying with the provider associated with the mishap. However, 68.4% of patients perceiving abandonment left their original provider; for them, post-error communication did not increase the probability of resolution. Abandonment accounted for half the post-event loss of trust in clinicians.Limitations Survey-based data may under-report the impact of perceived errors on vulnerable populations. Moreover, patients may not be cognizant of all forms of adverse events or all sequelae to those events. Our data were drawn from a single state and time period.Conclusion Addressing the deleterious impact of persisting abandonment merits attention in programmes responding to patient safety concerns. Enhancing patient engagement in the aftermath of an adverse medical event has the potential to reinforce therapeutic alliances between patients and their subsequent clinicians.

AbstractIn recent years, it has become clear that artificial intelligence (AI) models can achieve high accuracy in specific pathology‐related tasks. An example is our deep‐learning model, designed to automatically detect serous tubal intraepithelial carcinoma (STIC), the precursor lesion to high‐grade serous ovarian carcinoma, found in the fallopian tube. However, the standalone performance of a model is insufficient to determine its value in the diagnostic setting. To evaluate the impact of the use of this model on pathologists' performance, we set up a fully crossed multireader, multicase study, in which 26 participants, from 11 countries, reviewed 100 digitalized H&E‐stained slides of fallopian tubes (30 cases/70 controls) with and without AI assistance, with a washout period between the sessions. We evaluated the effect of the deep‐learning model on accuracy, slide review time and (subjectively perceived) diagnostic certainty, using mixed‐models analysis. With AI assistance, we found a significant increase in accuracy (p < 0.01) whereby the average sensitivity increased from 82% to 93%. Further, there was a significant 44 s (32%) reduction in slide review time (p < 0.01). The level of certainty that the participants felt versus their own assessment also significantly increased, by 0.24 on a 10‐point scale (p < 0.01). In conclusion, we found that, in a diverse group of pathologists and pathology residents, AI support resulted in a significant improvement in the accuracy of STIC diagnosis and was coupled with a substantial reduction in slide review time. This model has the potential to provide meaningful support to pathologists in the diagnosis of STIC, ultimately streamlining and optimizing the overall diagnostic process.

Context.— Urinary and Male Genital Tumours is the 8th volume of the World Health Organization Classification of Tumours series, 5th edition. Released in hard copy in September 2022, it presents an update to the classification of male genital and urinary tumors in the molecular age. Building upon previous volumes in this series, significant effort has been made to harmonize terminology across organ systems for biologically similar tumors (eg, neuroendocrine tumors). Genomic terminology has been standardized and genetic syndromes covered more comprehensively. This review presents a concise summary of this volume highlighting new entities, notable modifications relative to the 4th edition, and elements of relevance to routine clinical practice. Objective.— To provide a comprehensive update on the World Health Organization classification of urinary and male genital tumors, highlighting updated diagnostic criteria and terminology. Data Sources.— The 4th and 5th editions of the World Health Organization Classification of Tumours: Urinary and Male Genital Tumours. Conclusions.— The World Health Organization has made several changes in the 5th edition of the update on urinary and male genital tumors that pathologists need to be aware of for up-to-date clinical practice.

This note is a plea, a call to action to all of us in this specialty, but especially to the leadership. We need to discuss depression and suicide in pathology and laboratory medicine. Absent this discussion, we risk losing one of our own (again) to suicide, and we put our trainees and staff at risk of suffering the traumatic loss of a work-family member to suicide. When this happens, perhaps the astute leader will send out a supportive email and arrange for a visit from a mental health professional. Of course, none of us will avail ourselves of this service—we do not seek mental health assistance in private—and we are not about to do it in public. Many will suffer long-term effects ranging from prolonged grief reactions to full-blown depression, deterioration in work performance, burnout and disengagement, increased substance abuse, loss of personal relationships, and perhaps even attempted suicide, among others.That healthcare workers have an increased rate of suicidal ideation is broadly recognized. Emerging data suggest that our field may be at higher risk than other specialties. It has been documented that the field of pathology has the highest suicidal ideation among specialties at 13%,1 and low resilience levels.2 We have high depression rates, despite having “low burnout rates,”3 suggesting that the low burnout rates may be spurious. Those burned out are likely self-excluding from surveys (a “not missing at random” bias). Data document introversion4,5 and depression-type symptoms5,6 among pathologists, factors also linked to suicidality.Suicidality has long been known to have social roots, as identified in Durkheim’s7 seminal sociological study “Le Suicide,” and is thus heavily moderated by an individual’s social integration and regulation into a group. Thus, the field of pathology needs to look at itself and consider what in our specialty’s social structure puts our members at risk. Possibly, we receive a subset of medical students at risk. Our own (and others’) stereotyping of ourselves (scientific, factual, cold) may be a hard landing spot for many looking to belong.8,9 The climate is undoubtedly disheartening, with an increasing commoditization in pathology; the oft-repeated minimization of the specialty (“pathology professionals are not medical professionals”); the stigma and perceived low prestige of the specialty;10,11 the prevalent concern that as a non–patient contact specialty, pathologists will soon be obsolete and replaced by computers.9 The majority of us do not see the direct impact of our work for patients; rare is the case in which we hear the protective “thank you” that our clinical colleagues hear from patients. A sense of anomie, especially after the long slog and financial burdens of medical school, is not entirely misplaced.Chair persons and residency directors in pathology need to put depression and suicide central on their “well-being of the field” agenda, and we need to develop pathology-specific strategies to target the issue.12 Universal strategies—strategies designed to influence everyone (eg, organizational “awareness” strategies)—are not enough, not for a subspecialty “at risk” and not for one that gets lost in the larger structure of medicine. One of the authors, who is contacted not infrequently by individuals about suicide, has concern that suicide risk is seemingly higher in US medical graduates.13 This hypothesis should be explored most expeditiously, as it is consistent with data that recent immigrants show a lower incidence of suicide relative to long-term residents of a country. Implicated in this question are concerns of how US medical graduates adjust to the practice of pathology or develop resilience during residency training. How do these trainees adjust to a social structure where the plurality of cotrainees and attending physicians are culturally non-American, especially if trainees have chosen pathology because advisors have suggested pathology because it is “quiet, undemanding, and non–patient contact”?Whatever the drivers, we are morally obligated to discuss depression and suicide in pathology much in the way that other high-risk professions—such as law enforcement, firefighting, and the armed services—are so bound. We need to determine the true risk of depression and subsequent suicide in the field of pathology, and then develop programs to identify, help, and support those at risk. Regrettably, but necessarily, there are also no well-developed guidelines for supporting members of the profession when suicide occurs. We have provided a rough outline of recommendations to accomplish these goals (Table).Action is necessary now—a pathology program lost another recently—not 4 years since we lost one of ours. Pathologists need to embrace the spirit of the Lorna Breen Law16 and take active steps to embrace a wellness leadership process and culture within our profession. The field and practice of pathology can be isolating in healthcare systems; our leadership should proactively work to avoid isolationism in medicine and more effectively engage both patients and clinicians so as to reflect the value and impact of the work of pathologists.

Supplement 3: Baseline characteristics for the 105 women that underwent extensive sampling of the fallopian tube.

Supplement 1. Diagram describing the approach used for sampling of tissue blocks in Part 2 and Part 3 of the study.