Fulminant Myocarditis with Combination Immune Checkpoint Blockade.

Immune checkpoint inhibitors have improved clinical outcomes associated with numerous cancers, but high-grade, immune-related adverse events can occur, particularly with combination immunotherapy. We report the cases of two patients with melanoma in whom fatal myocarditis developed after treatment with ipilimumab and nivolumab. In both patients, there was development of myositis with rhabdomyolysis, early progressive and refractory cardiac electrical instability, and myocarditis with a robust presence of T-cell and macrophage infiltrates. Selective clonal T-cell populations infiltrating the myocardium were identical to those present in tumors and skeletal muscle. Pharmacovigilance studies show that myocarditis occurred in 0.27% of patients treated with a combination of ipilimumab and nivolumab, which suggests that our patients were having a rare, potentially fatal, T-cell-driven drug reaction. (Funded by Vanderbilt-Ingram Cancer Center Ambassadors and others.).

Differences in immunohistochemistry utilization by general and breast subspecialty pathologists at a large academic institution.

OBJECTIVES: Immunohistochemistry (IHC) can be a useful adjunct in diagnostic breast pathology, but best practices have not been clearly established. We sought to compare the patterns of p63 utilization between general pathologists (GP) and subspecialized breast pathologists (BP), analyze diagnostic discrepancy rates, and identify types of lesions requiring immunohistochemistry. METHODS: The pathology database was searched over 6-year period to identify breast needle core biopsy cases utilizing p63 and subsequent excision results. RESULTS: P63 was ordered more frequently by BP (2.3% of cores) compared to GP (1.1% of cores, p = 0.0005). The most frequent utilization of p63 by GP for benign lesions (44.0%) followed by invasive carcinomas (36.0%) while BP most frequently ordered p63 on invasive carcinomas (49.5%) and DCIS (26.6%). CONCLUSIONS: While IHC use may be thought to be most helpful to those with less experience or knowledge in breast pathology, these results suggest that utilization is increased with subspecialty training.

Intraoperative sentinel lymph node evaluation: Optimizing surgical pathology practices in an era of changing clinical management.

Axillary lymph node status is an independent prognostic indicator in breast cancer. Intraoperative identification of metastatic carcinoma in sentinel lymph nodes may allow for concurrent axillary lymph node dissection at the time of primary tumor excision. A retrospective review of patients undergoing primary breast cancer excision with sentinel lymph node sampling was performed. Sensitivity and specificity of imprint cytology (touch prep) with and without the incorporation of gross evaluation was determined using permanent section results as the gold standard. Five hundred sixteen lymph nodes were analyzed by imprint cytology in 213 patients, and 203 lymph nodes were analyzed in 74 patients incorporating gross examination. Sensitivity and specificity for the detection of macrometastases by touch prep alone were 60% and 99% respectively with 4 patients undergoing same-day axillary dissection for only micrometastatic disease. False negative causes included lack of transfer of malignant cells in 8 cases and misinterpretation of tumor cells in 6 cases. Incorporating gross examination in the modified protocol resulted in reduced sensitivity of 38%, but achieved the desired 100% specificity and positive predictive value. Imprint cytology alone did not reliably distinguish between micro- and macrometastatic disease. Gross assessment combined with imprint cytology allows for improved assessment of volume of axillary disease, but is an insensitive technique.

Novel Clinical and Pathologic Findings in a Heartland Virus-Associated Death.

We describe an investigation into a Heartland virus (HRTV)-associated death in Tennessee with novel clinical and pathologic findings. HRTV can cause rapidly fatal, widely disseminated infection with multisystem organ failure in patients without substantial comorbidities. We identified viral antigen in multiple organ tissues where it was not detected previously.

Sebaceous Carcinoma of the Middle Ear: A Case Report.

Here we present the first case of sebaceous carcinoma of the middle ear. We discuss the treatment course and post treatment results after 11 years of follow up. We further summarize the available literature of sebaceous carcinoma of the temporal bone, which prior to this case was exclusively limited to the external auditory canal. Laryngoscope, 134:3769-3772, 2024.

Cytology and LGBT+ health: establishing inclusive cancer screening programs.

There are substantial disparities in cancer screening for sexual minorities and gender non-conforming patients. In additional to patients having trauma due to negative experiences with the healthcare system, disparities may be heightened due to heteronormative and cisnormative design of screening programs and electronic medical record systems. Furthermore, there are morphologic challenges specific to certain specimen types from the LGBT + population, such as anal cytology samples, cervical cytology from transgender men taking testosterone, and neovaginal cytology samples. Men who have sex with men are at increased risk for anal cancer compared with the general population. While early detection of anal dysplasia decreases the risk of invasive carcinoma, screening programs are not widespread. Cervical cancer screening may be psychologically and physically challenging for transgender men and non-binary patients. The use of exogenous testosterone therapy causes atrophic changes in cervical cytology samples which mimic high-grade dysplasia. The rate of unsatisfactory samples are also increased in this population. Although HPV driven cancers have been reported in patients with neovaginas, there are currently no guidelines about appropriate screening for transgender women and intersex patients who have neovaginas. Cytopathologists can optimize the health of LGBT + patients in many ways including advocating for inclusive screening guidelines, validating self-collection for HPV and cytology samples, updating requisition forms to better capture the spectrum of gender expression, and recognizing the morphologic changes in cytology samples due to exogenous hormone use.

SALL-4 and Beta-Catenin Expression in Sinonasal Teratocarcinosarcoma.

Sinonasal teratocarcinosarcoma (SNTCS) is a rare, aggressive malignancy that displays a heterogeneous combination of malignant blastema-like, epithelial and mesenchymal components. Its exact histogenesis is unknown with hypotheses ranging from true germ cell derivation to origin from pluripotent stem cells. However, despite this tumor's multiphenotypic histology, which includes frequent glandular, squamous, and neuroectodermal differentiation similar to adnexal germ cell tumors, SNTCS appears to have some differences from adnexal teratomas. For example, unlike adnexal teratomas, SNTCS has never been described as a component in a mixed germ cell tumor. Accurate recognition of SNTCS is difficult due to its rarity and histologic overlap with other sinonasal tumors. It is even more problematic on biopsy, since not all elements may be present in small samples. SNTCS can also share similar staining patterns with other neoplasms in the differential diagnosis. A recent study found nuclear ß-catenin expression in a single TCS, but this has yet to be confirmed in additional cases. SALL-4, a marker of germ cell tumors, has not been examined. We performed ß-catenin and SALL-4 immunohistochemistry on whole sections of 7 SNTCS and 19 other sinonasal neoplasms to assess whether ß-catenin and SALL-4 are of utility in establishing a diagnosis of SNTCS. Intensity of expression and percentage of staining was noted for each tumor. For SNTCS, distribution of staining within each histologic component (immature neuroectodermal, epithelial, and mesenchymal) was also documented. Nuclear ß-catenin expression was not identified in any SNTCS, with all cases demonstrating membranous expression (6 cases) or cytoplasmic and membranous expression (1 case). SALL-4 immunohistochemistry, however, was relatively sensitive (85.7%) and specific (89.5%) for SNTCS. SALL-4 expression was also identified in one poorly differentiated neuroendocrine carcinoma and one case of sinonasal undifferentiated carcinoma. SALL-4 appears to have utility in distinguishing SNTCS from other high grade sinonasal tumors.

Nondiagnostic category of Milan System for Reporting Pediatric Salivary Gland Cytopathology: outcomes and root cause analysis.

BACKGROUND: Fine-needle aspiration (FNA) results classified as the nondiagnostic category of the Milan system for reporting salivary gland cytopathology (MSRSGC) may be infrequently encountered in children. Clinical management may be challenging due to lack of data regarding outcomes and underlying causes. METHODS: We retrospectively analyzed 106 consecutive pediatric salivary gland FNAs (2000-2020; 45% performed under image guidance). The outcomes of patients with nondiagnostic results were analyzed. Clinical parameters, FNA procedural parameters, and histopathologic parameters were compared between diagnostic and nondiagnostic cases. A root cause analysis was performed using the fishbone diagram and the 5 Whys method. RESULTS: A total of 103 initial FNAs were identified. The nondiagnostic rates for initial and repeat biopsy were 16% (16/103) and 67% (2/3), respectively. Initial nondiagnostic FNAs were most frequently managed by clinical/radiologic follow-up only (56%, 9/16), followed by direct surgery (19%, 3/16) and repeat FNA (19%, 3/16). By histologic and clinical/radiologic follow-up, the risk of malignancy for nondiagnostic cases was zero. Palpation guidance (P < .05), inadequate sampling determined by rapid on-site evaluation (P < .01), and lesions with cystic, vascular, or diffuse nature (P < .05) were significantly associated with nondiagnostic results. By root cause analysis, proceduralist sampling error and lack of ultrasound guidance were the most common primary and secondary causes, respectively. CONCLUSIONS: Pediatric salivary gland lesions of the nondiagnostic MSRSGC category have minimal risk of malignancy and may be successfully managed by clinical/radiologic follow-up. The root causes for nondiagnostic results were often multifactorial and primarily related to proceduralist sampling, characteristics of the lesions, and lack of ultrasound guidance.

Adrenal gland cytology reporting: a multi-institutional proposal for a standardized reporting system.

BACKGROUND: With the development of new technologies and the changing patient profiles, cytopathology departments receive increasing numbers of adrenal gland cytology specimens. In this study, the authors analyzed archival adrenal gland cytology cases and attempted to implement a diagnostic reporting system. DESIGN: Retrospective electronic medical record search was performed for adrenal gland cytology specimens in seven tertiary care centers. The cytology diagnoses were grouped in 7 categories: nondiagnostic, nonneoplastic, benign adrenal cortical elements (BACE), primary neoplasm of noncortical origin (NONC), atypia of undetermined significance (AUS), suspicious for malignancy (SM), and malignant (MAL). If available, histopathology results of concurrent and/or follow-up biopsies and/or resections were documented. RESULTS: A total of 473 adrenal gland cytology cases were included. BACE cases comprised 21.8%, whereas MAL cases were 57.5% of all cases. For BACE and MAL categories, there were 100% and 98.9% correlation, respectively, in the cases with histopathology follow-up. Six of 10 NONC cases had histopathology diagnoses and there were 3 pheochromocytomas and 3 schwannomas. Twenty-one AUS cases had histology follow-up and 10 (47.6%) of them were malignant. Six cases of SM had histopathology follow-up, and all of them were malignant on the follow-up. CONCLUSIONS: The authors propose a 7-tier diagnostic scheme for adrenal gland cytology. The risk of malignancy was 98.9% in MAL cases (87/88) in the cohort. The only case with discordance was reported as "adrenal cortical adenoma with marked atypia"' on resection. There was no difference between endoscopic ultrasound-guided and percutaneous methods. Further studies are needed to validate and make this approach universal.

The Utility of Perilipin in Liposarcomas: PLIN1 Differentiates Round Cell Liposarcoma From Other Round Cell Sarcomas.

Liposarcoma is the most common soft tissue sarcoma in adults; however, accurate diagnosis often depends on the use of ancillary molecular testing which can be time consuming and expensive. Myxoid/round cell liposarcoma may be a diagnostic challenge due to the morphologic similarities with other nonadipocytic sarcomas with round cell morphology. Immunohistochemistry may be a helpful adjunct to appropriately triage cases for molecular testing. Perilipin 1 (PLIN1) and perilipin 2 (adipophilin) (PLIN2) are intracellular proteins involved in lipid droplet formation, which we hypothesized may be useful as immunohistochemical markers for liposarcoma. Using archival tumor tissue, we assessed pattern of PLIN1 and PLIN2 expression in 46 adipocytic tumors and 36 nonadipocytic sarcomas. PLIN1 was expressed in 88% of liposarcomas, including 100% of myxoid/round cell liposarcomas, and did not have any expression in nonadipocytic sarcomas. PLIN1 was not expressed in dedifferentiated liposarcoma. Although PLIN2 demonstrates increased sensitivity for liposarcoma, including expression in dedifferentiated liposarcoma, it is not specific for adipocytic differentiation and is expressed in other nonadipocytic sarcomas. Furthermore, PLIN2 is not expressed in lipoma-like well-differentiated liposarcoma, and as such has limited diagnostic utility.

Targeted education as a method for reinforcing Paris System criteria and reducing urine cytology atypia rates.

INTRODUCTION: The Paris System for Urine Cytology (TPS) provides well-defined diagnostic criteria for the category of atypical urothelial cells (AUC). The current study compares the rate of AUC diagnoses at a large academic medical center before and after an educational intervention (EI) by a urine cytology expert. MATERIALS AND METHODS: An expert in TPS delivered an educational intervention consisting of an interactive microscope session and a didactic session that focused on the AUC diagnostic category. The number of urine cytology cases, the AUC rate, and the false-negative percentage were calculated before and after the EI, using the electronic medical records and cytologic-histologic correlation records. RESULTS: A total of 4026 urine cytology cases were signed out in the 25 months prior to the educational intervention and 1585 cases were signed out in the 10 months after the intervention. EI had a significant impact on diagnostic categorization, including a reduction in AUC (19.6% versus 12.5%) and suspicious for high-grade urothelial carcinoma (3.9% versus 3.1%) diagnoses. The cytotechnologists also placed fewer cases into the AUC category during primary screening (27.6% versus 23.0%). Although a higher percentage of cases was reported as negative for high-grade urothelial carcinoma, the false-negative rate did not significantly change after the intervention (1.8% versus 2.0% of negative cases, P = 0.65). CONCLUSIONS: Focused educational sessions for pathologists and cytotechnologists on the diagnostic criteria for AUC as defined by TPS can significantly reduce the rate of atypical diagnoses without a significant increase in the rate of false negatives.

Fine needle aspiration of salivary gland carcinomas with high-grade transformation: A multi-institutional study of 22 cases and review of the literature.

BACKGROUND: High-grade transformation (HGT) is a rare process whereby conventional low- to intermediate-grade salivary gland carcinomas (SGC) transform into high-grade, poorly or undifferentiated malignancies with focal or complete loss of their conventional histomorphologic features. Because tumors with HGT are associated with a worse prognosis than their conventional counterparts, preoperative recognition of HGT may be of benefit for optimal patient management. Using a multi-institutional approach, we describe the largest fine needle aspiration (FNA) cohort of salivary gland carcinomas with HGT. METHODS: The archives of 9 large academic medical centers were searched, and 22 cases of SGC with HGT were identified by surgical excision accompanied by preoperative FNA. Clinical and cytomorphologic features were retrospectively reviewed. RESULTS: The male-to-female ratio was 14:8, and the mean patient age was 60.2 years. The average tumor size was 3.6 cm, and 19 cases were from the parotid gland. Acinic cell carcinoma with HGT was the most common tumor subtype, comprising 12 cases with HGT, followed by adenoid cystic carcinoma, secretory carcinoma, and other subtypes. Eighteen cases were classified as malignant; however, a specific diagnosis of HGT was not made. Sixteen cases contained a high-grade cytologic component, and 7 cases had a mixture of both conventional and high-grade components retrospectively. CONCLUSIONS: SGC with HGT should be considered in the differential diagnosis of a salivary gland aspirate exhibiting high-grade cytomorphologic features. The presence of distinct tumor populations, conventional and high-grade, should prompt consideration of HGT, especially when the conventional component is acinic cell carcinoma or adenoid cystic carcinoma.

Evidence-based Tumor Staging of Skeletal Chondrosarcoma.

The eighth edition of the American Joint Committee on Cancer (AJCC) staging system has introduced major changes for the staging of skeletal sarcomas. However, it is unclear if these changes improve the predictive value for chondrosarcomas of the nonpelvic appendicular and nonspinal axial skeleton. Specifically, there is no clear evidence that supports the use of the proposed binary size cutoff of 8 cm for risk stratification, nor is a rationale provided for the categorization of grade 2 chondrosarcomas as high grade. The prognostic value of various anatomic and pathologic factors including tumor size, histologic grade, site of metastasis, and local tumor extent was evaluated using a cohort of patients derived from the National Cancer Database (N=3946). A simplified evidence-based staging system for chondrosarcoma (the Vanderbilt Staging System) was developed based on histologic subtype, histologic grade, and presence of metastatic disease. The predictive accuracy for 5-year overall survival was evaluated for the AJCC 8th edition, Musculoskeletal Tumor Society, and Vanderbilt Staging Systems by comparing areas under receiver operating characteristic curves generated from logistic regression analysis. Three different concordance indices and Bayesian information criterion were also calculated for model comparisons. The Vanderbilt Staging System showed significantly improved predictive accuracy for 5-year survival (82±2%) compared with the AJCC (79±2%; P=0.0075) and Musculoskeletal Tumor Society systems (76±2%; P<0.00005) in a separate validation cohort. Furthermore, the Vanderbilt Staging System showed significantly higher concordance with clinical outcomes for 2 of 3 examined indices and significantly greater extent of explained variation compared with the other 2 staging systems.

Clinical characterization of colitis arising from anti-PD-1 based therapy.

Colitis is a frequent, clinically-significant immune-related adverse event caused by anti-programmed death-1 (PD-1). The clinical features, timing, and management of colitis with anti-PD-1-based regimens are not well-characterized. Patients with advanced melanoma that received either anti-PD-1 monotherapy ("monotherapy") or combined with ipilimumab ("combination therapy") were screened from 8 academic medical centers, to identify those with clinically-relevant colitis (colitis requiring systemic steroids). Of 1261 patients who received anti-PD-1-based therapy, 109 experienced colitis. The incidence was 3.2% (30/937) and 24.4% (79/324) in the monotherapy and combination therapy cohorts, respectively. Patients with colitis from combination therapy had significantly earlier symptom onset (7.2 weeks vs 25.4 weeks, p < 0.0001), received higher steroid doses (median prednisone equivalent 1.5 mg/kg vs 1.0 mg/kg, p = 0.0015) and experienced longer steroid tapers (median 6.0 vs 4.0 weeks, p = 0.0065) compared to monotherapy. Infliximab use and steroid-dose escalation occurred more frequently in the combination therapy cohort compared to monotherapy. Nearly all patients had resolution of their symptoms although one patient died from complications. Anti-PD-1 associated colitis has a variable clinical presentation, and is more frequent and severe when associated with combination therapy. This variability in checkpoint-inhibitor associated colitis suggests that further optimization of treatment algorithms is needed.

Duplicate Type and Screen Testing: Waste in the Clinical Laboratory.

CONTEXT: - In the United States, approximately $65 billion dollars is spent per year on clinical laboratory testing, of which 20% to 30% of all testing is deemed inappropriate. There have been multiple studies in the field of transfusion medicine regarding evidence-based transfusion practices, but limited data exist regarding inappropriate pretransfusion testing and its financial and clinical implications. OBJECTIVE: - To assess duplicative testing practices in the transfusion medicine service. DESIGN: - A 24-month retrospective review was performed at a 1025-bed tertiary care center, identifying all duplicate type and screen (TS) tests performed within 72 hours of the previous TS. Duplicative testing was classified as appropriate or inappropriate by predetermined criteria. The level of underordering was analyzed through a query of the electronic event reporting system. A cost analysis was performed to determine the financial impact of inappropriate duplicative TS. RESULTS: - The mean rate of inappropriate, duplicative TS orders was 4.13% (standard deviation ± 4.09%). Rates of inappropriate ordering ranged from 0.01% to 15.5% depending on the clinical service and did not correlate with volume of tests ordered. There were 8 reported cases of delayed blood delivery due to lack of a valid TS during the study period, demonstrating that underordering is also a harmful practice. The laboratory cost of inappropriate testing for the study period was $80,434, and phlebotomy costs were $45,469. CONCLUSIONS: - Our study demonstrates that inappropriate TS ordering is costly, both financially and clinically. By evaluating the percentage of inappropriate TS tests by clinical services, we have identified services that may benefit from additional education and technologic intervention.