Immunohistochemical Criteria Research Articles

Chordoma: Site-Wise Predilections and Pathological Tenets

Abstract Background: Chordomas are rare tumours of presumptive notochordal origin, mostly occurring in the axial skeleton of the body. These tumours are slow growing but are locally invasive neoplasms. Diagnosis requires qualification of the radiological, histopathological, and immunohistochemical criteria. Management predominantly comprises surgical resection with negative margins. Objective: Our study aimed to analyse the clinico-pathological spectrum of these rare chordoma cases visiting our tertiary care institute. Materials and Methods: The study was retrospective, comprising chordoma cases reported histopathologically between January 01, 2013, and August 31, 2023 (a total period of 10.5 years). Clinico-radiological data were recorded. Histopathological diagnosis was separately reviewed by two pathologists. All data were statistically analysed. Results: In total, 41 chordoma cases were received, with a mean age of 43.2 + 17.4 years (6–72 years). Male:female ratio was 1.2:1. Spheno-occipital region chordomas (27 cases) were most common, followed by sacrococcygeal (8 cases) and vertebral (6 cases) chordomas. Symptoms varied with location. However, the commonest presenting complaint was pain. These region-wise chordoma categories were statistically compared in terms of patients’ age, male:female ratio, symptomatic duration, tumour size, histopathological tumour type, and recurrence on follow-up. Of these, only patients’ age and tumour size were found to be statistically significant (P value was 0.011 and 0.0004, respectively). Conclusion: Clinico-pathological parameters vary with the anatomical location of chordoma. We present the experience of this rare tumour in terms of clinico-radiopathological features visiting our tertiary care institute in northern India.

Comparison of diagnostic algorithms in clinically suspected viral myocarditis: agreement between cardiac magnetic resonance, endomyocardial biopsy and troponin T

AimsMyocardial inflammation is increasingly detected non-invasively by tissue mapping with cardiovascular magnetic resonance (CMR). Intraindividual agreement with endomyocardial biopsy (EMB) or marker of myocardial injury, high-sensitive troponin (hs-cTnT) in patients with clinically suspected viral myocarditis not understood. Methods and resultsProspective multicentre study of consecutive patients with clinically suspected myocarditis who underwent blood testing for hs-cTnT, CMR and EMB as a part of diagnostic work-up. EMB was considered positive based on immunohistological criteria in line with the ESC definitions. CMR diagnoses employed tissue mapping using sequence-specific cut-off for native T1 and T2 mapping; active inflammation was defined as T1≥2SD and T2≥2SD above the mean of normal range. Hs-cTnT of greater than 13.9ng/1 was considered significant. A total of 114 patients (age (mean±SD) 54±16, 65% males) were included, of which 79(69%) had positive EMB-criteria, 64(56%) CMR criteria, and a total of 58 (51%) positive troponin. Agreement between EMB and CMR diagnostic criteria was poor (CMR vs. ESC: AUCs: 0.51 (0.39-0.62)). The agreement between the significant hs-cTnT rise and CMR-based diagnosis of myocarditis was good (AUC: 0.84 (0.68-0.92); p<0.001), but poor for EMB (0.50 (0.40-0.61). Hs-cTnT was significantly associated with native T1 and T2, hs-CRP and NT-pro BNP (r=0.37, r=0.35, r=0.30, r=0.25 p<0.001), but not immunohistochemical criteria or viral presence. ConclusionsIn clinically suspected viral myocarditis, all diagnostic approaches reflect the pathophysiological elements of myocardial inflammation, however the differing underlying drivers only partially overlap. The EMB and CMR diagnostic algorithms are neither interchangeable in terms of interpretation of myocardial inflammation nor in their relationship with myocardial injury.

Development of Non-Invasive miRNA Markers for Assessing the Quality of Human Induced Pluripotent Stem Cell-Derived Retinal Organoids.

Human retinal organoids (ROs) have emerged as valuable tools for studying retinal development, modeling human retinal diseases, and screening drugs. However, their application is limited primarily due to time-intensive generation, high costs, and low reproducibility. Quality assessment of RO differentiation is crucial for their application in research. However, traditional methods such as morphological evaluation and immunohistochemical analysis have limitations due to their lack of precision and invasiveness, respectively. This study aims to identify non-invasive biomarkers for RO differentiation quality using exosomal microRNAs (miRNAs), which are known to reflect cell-specific functions and development in the retina. We differentiated ROs from human induced pluripotent stem cells (hiPSCs) and classified them into 'superior' and 'inferior' groups based on morphological and immunohistochemical criteria. Exosomes from the conditioned media were isolated and analyzed for miRNA content. Our findings revealed distinct miRNA profiles between superior and inferior ROs, with superior ROs exhibiting higher miRNA diversity and specifically up- or down-regulated miRNAs. Gene ontology and pathway enrichment analyses indicated that the target genes of these miRNAs are involved in neuron proliferation and differentiation. The study suggests the potential of exosomal hsa-miR-654-3p and hsa-miR-451a as non-invasive biomarkers for real-time monitoring of RO quality, facilitating the development of standardized, efficient, and cost-effective culture methods.

P-302 Oral ofloxacin combined with vaginal metronidazole for chronic endometritis: a prospective open-label cohort study

Abstract Study question Does oral ofloxacin 2x200 mg for 10 days combined with vaginal metronidazole 1x500 mg for 10 days reduce the activity of chronic endometritis? Summary answer The investigated antibiotics may be beneficial in some cases of chronic endometritis, except in cases of concomitant endometrial polyp, where they adversely affect treatment outcome. What is known already Chronic endometritis (CE) is characterized by the presence of atypical plasma cell infiltrates (CD138 positive) in the endometrial stroma. CE may adversely affects fertility by reducing endometrial receptivity, impairing decidualization and uterine contractility, thus increasing the risk of recurrent pregnancy loss and implantation failure. Some idiopathic infertility cases are attributed to CE. The diagnostics of CE is challenging because the clinical evaluation is nonspecific and the immunohistochemical criteria are not consistent between research centers. Literature data suggested that successful treatment of CE with antibiotics could improve live birth rates, but a preferred treatment regimen has not been identified. Study design, size, duration A prospective cohort study included women undergoing office hysteroscopy (OH) at a tertiary referral center in 2021-2023. Women diagnosed with CE were assigned, based on their preference, to the intervention arm of ofloxacin 2x200 mg orally for 10 days + metronidazole 500 mg vaginally for 10 days or to the control arm (no antibiotics). 100 women underwent repeated hysteroscopy after 3 cycles, of which 77 received antibiotics and 23 were controls. Participants/materials, setting, methods Women aged 18-45 who met eligibility criteria for OH were included. Karl Storz 5.0 mm Bettocchi® operating sheath with a 2.9 mm 30° telescope and a 5Fr working channel was used. Endometrial lesions or biopsy specimens were collected with grasping forceps, blunt scissors or bipolar needle electrode. Saline was used as the dilating medium. Tissue samples were subjected to histopathological examination. Plasma cells were detected by immunohistochemical staining with Monoclonal Mouse Anti-Human CD138 antibodies. Main results and the role of chance The most common findings identified at hysteroscopy were endometrial polyps (43%), polypoid endometrium (38%), micropolyps (23%), focal (27%) and diffuse hyperemia (18%) and cesarean scar defect (14%). CE was defined as the presence of &amp;gt; 2 plasma cells/mm2. The Mann-Whitney U test showed a significantly higher plasma cell count (PCC) in the presence of a cesarean scar defect than in other cases (23 vs. 18/mm2, p = 0.031) and a tendency towards a lower PCC in micropolyps (9 vs. 21/mm2, p = 0.063). The correlation of hysteroscopic findings with CE activity was weaker than expected. Using repeated measures ANOVA, no difference in PCC between primary and follow-up hysteroscopy was found in either arm (p = 0.8), while post-hoc tests showed that the mean PCC decreased from 12 to 5/mm2 (p = 0.02) in the intervention arm, and from 14 to 6 (p = 0.23) in the control arm. On follow-up hysteroscopy, polyp remission was observed significantly more often in the control arm than in the intervention arm (61% vs. 27%, pChi2=0.02), in which de novo polyp was observed in 4%. In polypoid endometrium, the remission rate was similar in both arms (19% vs. 22%), and the rate of de novo lesions was significantly lower in interventional arm (16% vs. 39%, pChi2=0.035). Limitations, reasons for caution The limitations include the small sample size, the CE definition based on the number of plasma cells calculated using the Receiver Operating Characteristic curve for the purposes of the study, and the empirical selection of antibiotic therapy. Wider implications of the findings Due to the weak correlation of hysteroscopic findings with CE activity, the diagnostics and treatment of CE based on clinical evaluation of the uterine cavity is not justified. Poorly selected antibiotic therapy may adversely affect the outcomes of treatment. Trial registration number 1072.6120.322.2020

Quality Assurance Model for Breast Cancer Prognostication Using the Modified Magee Equations.

The Oncotype DX recurrence score (RS) is a widely used test that provides prognostic information on the likelihood of disease recurrence and predictive information on the benefit of chemotherapy in early-stage, hormone receptor-positive breast cancer. Despite its widespread use, quality assurance of the RS does not receive the same level of scrutiny as other tests, such as human epidermal growth factor receptor 2 (HER2) immunohistochemistry. To use modified Magee equations to calculate Magee score (MS) as a quality check of RS. The MS is an easily accessible prognostic model that uses histopathologic and immunohistochemical criteria. We identified cases where the RS and MS differed by 10 points or more or were in different risk categories. These instances were considered significant discordances. MS was presented along with RS at multidisciplinary tumor boards and all discrepancies were discussed to determine clinical significance and appropriate next steps. Twenty-five of 155 cases (16.1%) had discrepancies between RS and MS. Of these 25 cases, 3 (12%) had problems with either the RS or the histopathologic interpretation. Among the cases with concordant RS and MS, no RS or interpretive problems were identified. Use of the MS as a quality control check for the RS can help ensure appropriate treatment decisions in breast cancer patients. Pathologists can play a key role in ensuring the quality of molecular-based prognostic scores by using histopathologic models to ensure accurate risk stratification and improve clinical outcomes.

Proliferation activity and hormonal status of atypical hyperplasia and endometrioid adenocarcinoma of the endometrium

Atypical hyperplasia of the endometrium is a precancerous condition for endometrioid adenocarcinoma of the endometrium, which is the largest group among malignant neoplasms of the uterine body, according to the Cancer Registry, the mortality rate from which took the 3rd place in 2021. The absence of specific clinical manifestations complicates diagnostics at the early stages of the process, which necessitates the study of histological and immunohistochemical criteria to verify the diagnosis. The aim of the study. To improve the differential diagnostic morphological and immunohistochemical criteria for the diagnosis of atypical hyperplasia and endometrioid adenocarcinoma of the endometrium, using the latest international classification data. Materials and methods. Retrospective analysis of 76 cases of postoperative material of women for the period from 2020 to 2022 with a diagnosis of “endometrioid adenocarcinoma of the endometrium” – 61 cases and “endometrial hyperplasia with atypia” – 15 included an assessment of histological, immunohistochemical features, followed by statistical processing of the obtained results. Results. The incidence of endometrioid adenocarcinoma of the endometrium and atypical endometrial hyperplasia occurs in the premenopausal and menopausal periods. The expression level of the Ki-67 marker is directly proportional to the degree of tumor malignancy (p &lt; 0.05). Estrogen receptors decrease as the degree of tumor malignancy increases. Progesterone receptors are equally present in endometrioid adenocarcinomas and atypical endometrial hyperplasia (p &lt; 0.05). Conclusions. The necessity of using the Ki-67 marker and determining the hormonal status in endometrioid adenocarcinomas of the endometrium and atypical hyperplasia of the endometrium is argued.

Morphological and immunohistochemical prognostic criteria for small cell lung cancers

Morphological and immunohistochemical prognostic criteria for small cell lung cancers

Cutaneous lymphoproliferative disorders: Back to the future.

In the 1980s, immunohistochemistry and clonality analyses became instrumental in the recognition and definition of new types of cutaneous T-cell lymphoma (CTCL) and cutaneous B-cell lymphoma (CBCL) and the development of new classifications. By accepting loss of pan-T-cell antigens and clonal T-cell receptor gene rearrangements as important criteria to differentiate between benign and malignant T-cell proliferations, and monotypic immunoglobulin light-chain expression and clonal immunoglobulin gene rearrangements as crucial criteria to distinguish between benign and malignant B-cell proliferations, many cases, until then diagnosed as cutaneous lymphoid hyperplasia or pseudolymphoma, were reclassified as primary cutaneous CD4+ small/medium T-cell lymphoma (PCSM-TCL) or primary cutaneous marginal zone lymphoma (PCMZL), respectively. However, in recent years there is growing awareness that neither these immunohistochemical criteria nor demonstration of T-cell or B-cell clonality is specific for malignant lymphomas. In addition, many studies have reported that these low-grade malignant CTCL and CBCL have an indolent clinical behavior and an excellent prognosis with disease-specific survival rates of or close to 100%. As a result, recent classifications have downgraded several low-grade malignant cutaneous lymphomas to lymphoproliferative disorder (LPD). Both the 5th edition of the WHO classification (2022) and the 2022 International Consensus Classification (ICC) of mature lymphoid neoplasms reclassified PCSM-TCL as primary cutaneous CD4+ small/medium T-cell LPD and primary cutaneous acral CD8+ T-cell lymphoma as primary cutaneous acral CD8+ T cell LPD. While the 2022 ICC introduced the term "primary cutaneous marginal zone LPD," in the 5th edition of the WHO classification PCMZL is maintained. In this review we describe the background and rationale of the continually changing terminology of these conditions and discuss the clinical consequences of downgrading malignant lymphomas to LPDs.

Sudden Death Due to Concurrent Arrhythmogenic Cardiomyopathy and Myocarditis: An Autopsy Case

Arrhythmogenic cardiomyopathy (ACM) is a rare genetically determined myocardial disease characterized by fibrofatty substitution of the myocardium which predisposes the patient to sudden cardiac death (SCD). In addition to the classic pathology seen in ACM, inflammatory infiltrates have been occasionally reported, suggesting a close pathophysiological relationship between ACM and inflammation. Evidence indicates that this inflammation is related to electrical instability resulting in ventricular tachycardia and SCD. This is an autopsy case of a 52-year-old female who died suddenly of concomitant ACM and myocarditis, fulfilling both histological and immunohistochemical diagnostic criteria. With the features of fatty variant ACM, the inflammatory infiltrate was prominent in the subendocardial layer of the left ventricle and was composed of mostly CD3-positive lymphocytes as well as some neutrophils and macrophages. In forensic practice, this case highlights the necessity of collecting multiple representative portions of cardiac tissue to search for inflammation, which can easily explain the cause of death and the dying process in ACM.

Assessment of specificity of dermatopathologic criteria for IgG4-related skin disease.

IgG4-related disease (IgG4-RD) represents a recently characterized multisystemic fibroinflammatory condition that can manifest a spectrum of skin findings (IgG4-related skin disease; IgG4-RSD). Histopathologic and immunohistochemical criteria have been proposed; however, the specificity of these criteria merits scrutiny given the potential histopathologic overlap of IgG4-RSD and both neoplastic and inflammatory skin conditions featuring lymphoplasmacytic infiltrates (IgG4-RSD mimics). This study sought to assess the specificity of the criteria by quantifying the frequency by which an expanded spectrum of IgG4-RSD mimics meet proposed thresholds. Following IRB approval, a total of 69 cases of IgG4-RD mimics, representing 14 different diagnoses featuring plasma cells, were reviewed and analyzed for the following histopathologic and immunohistochemical features: (i) maximum IgG4+ count/high-powered field (hpf) >200; (ii) IgG4/IgG ratio >0.4 averaged over 3 hpfs; (iii) IgG4+ count >10 per hpf. Screening for IgG4-RSD by histopathologic criteria demonstrated the high frequency of lymphoplasmacytic infiltrates, contrasted with the rarity of storiform fibrosis (only one case of erythema elevatum diutinum [EED]) and obliterative phlebitis (0 cases). By immunohistochemical criteria, the analysis revealed that no cases exceeded 200 IgG4+ cells; 13% (9/69) cases demonstrated an IgG4/IgG ratio of >0.4 averaged over 3 hpfs; and 23% (16/69) cases demonstrated a mean IgG4+ count of >10 per hpf. Application of proposed IgG4-RSD histopathologic criteria to an expanded spectrum of potential IgG4-RSD mimics (to include cutaneous marginal zone lymphoma, syphilis, necrobiosis lipoidica, lichen sclerosus, ALHE, psoriasis, lymphoplasmacytic plaque, EED, and erosive pustular dermatosis), highlights the relative nonspecificity of lymphoplasmacytic infiltrates contrasted with the stringency of storiform fibrosis and obliterative fibrosis. Furthermore, an IgG4+ cell count of >10 per hpf and an IgG4/IgG ratio of >0.4 are not specific to IgG4-RSD alone. In the appropriate clinical context for IgG4-RSD, histopathologic features still represent the entry threshold for diagnosis consideration, which then allows for further screening by immunohistochemical criteria.

Comparison and Development of Immunohistochemical Diagnostic Criteria for Blastic Plasmacytoid Dendritic Cell Neoplasm

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare hematological malignancy derived from the precursors of plasmacytoid dendritic cells. Diagnostic criteria for BPDCN have not been fully established. BPDCN is often diagnosed without other BPDCN markers than the 3 conventional markers (CD4, CD56, and CD123) in practice and case reports, although acute myeloid leukemia/myeloid sarcoma (AML/MS), which is always considered in the differential diagnosis of BPDCN, can express them. We reviewed published case reports on BPDCN and found that the diagnosis was made without any other BPDCN markers than the conventional markers in two-thirds of the cases. Next, 4 representative existing diagnostic criteria were applied to 284 cases of our cohort of BPDCN and mimics. The results differed in 20% (56/284) of the cases. The criterion based on the 3 conventional markers alone had a low concordance rate (80%-82%) with the other 3 criteria, which were almost concordant with each other. However, newly found minor limitations in these criteria prompted us to devise new diagnostic criterion for BPDCN composed of TCF4, CD123, TCL1, and lysozyme. We also revealed that CD123-positive AML/MS patients had a significantly poorer outcome than those with BPDCN and that 12% (24/205) of the cases were non-BPDCN even if all 3 conventional markers were positive, thus clarifying the risk of diagnosing BPDCN without more specific markers. In addition, histopathological features, such as the reticular pattern, which is not seen in BPDCN and suggests AML/MS, were also identified.

Differentiated, immunobased approach of anaplastic large cell lymphoma treatment in children and adolescents: literature review and protocol ALCL-NII DOG-2003 results

Background. Anaplastic large cell lymphoma (ALCL) is a rare variant of highly aggressive lymphomas in children and adolescents. ALCL is characterized by a heterogeneous clinical manifestation with nodal and extranodal lesions, various morphological variants, variable expression of T-cell markers and cytogenetic aberrations involving the ALK gene. Due to the rarity of this disease (up to 10–15 % of all non-Hodgkin’s lymphomas in children), there are no uniform standards for ALCL therapy. Block treatment schemes similar to those applied in the treatment of B-cell non-Hodgkin’s lymphomas are used; less often there can be used protocols similar to the therapy of acute lymphoblastic leukemia. Taking into account the unfavorable effect on the prognosis of T-cell markers expression in ALCL, we developed protocol ALCL-NII DOG-2003, which considered the immunological features of the tumor.Aim. To assess the effectiveness of differentiated immunobased ALCL therapy by domestic protocol ALCL-NII DOG-2003.Materials and methods. From 01.03.1997 to 01.10.2022, 60 patients with primary diagnosed ALCL were included in the study. The diagnosis was based on histological, immunohistochemical and cytogenetic criteria of WHO classification of hematopoietic and lymphoid tissues tumors. According to treatment program, patients were subdivided in 2 groups: patients treated by NHL-BFM 95 protocol (n = 21) and by ALCL-NII DOG-2003 (n = 39). The male:female ratio was 1,3:1 in group of patients with NHL-BFM 95 protocol and 1,4:1 – in ALCL-NII DOG 2003. The effectiveness assessment was based on overall, event-free and relapse-free survival with SPSS 21.0 computed program. The differences between groups were significant with p ≤0.05.Results. The use of risk-adopted, immuno-oriented protocol made it possible to obtain a 10‑year EFS in 97.4 ± 2.6 %, whereas results of the standard NHL-BFM 95 protocol are 63.9 ± 10 % (p = 0.001).Conclusion. The use of a differentiated approach to ALCL treatment, considering not only the stage and prognostic risk group, but also the immunological features of the tumor, is more effective, and allows achieving significantly higher survival rates, than standard program (NHL-BFM 95).

P370 INCIDENCE AND MAIN CLINICAL CHARACTERISTICS OF MYOCARDITIS IN PIACENZA PROVINCE IN THE LAST FIVE YEARS

Abstract Myocarditis is an inflammatory disease of cardiac muscle caused by a variety of etiologies, myocardial involvement and clinical presentations ranging from chest pain to extreme conditions such as cardiogenic shock or death. The variability in presentation reflects the variability in histological disease severity, etiology, and disease stage at presentation. The diagnosis may be suspected by clinical and noninvasive features and is confirmed by endomyocardial biopsy by established histologic, immunologic, and immunohistochemical criteria. CMR imaging is a valid diagnostic support which can detect important myocarditis features from evidence of inflammatory hyperemia and edema to myocardial scar. Due to its clinical presentation and the absence of a safe sensitive non–invasive diagnostic tool, the frequency of this condition and its specific etiology is often difficult to identify, and because of this, the cause is frequently unknown. Anyway among the infectious etiologies, viruses are the presumed to be the most frequent pathogens. We analyzed the main clinical features of patients who were hospitalized for myocarditis in our province in the past five years. Since 2018, 53 patients received a diagnosis of myocarditis. Mean age was 38, 40 (75%) of them were males. The vast majority of patients underwent CMR as a part of diagnostic work–up and we found lateral wall as the most frequently involved. Almost half of the patients showed oedema as a sign of acute inflammation and 35% had more than one segment affected. Mean ejection fraction was 60%. 22 of them were discharged as having as “idiopathic”, 18 had a viral cause (of which 2 were clearly COVID–related) with gastroenteritis being the most common clinical presentation. Of note, only one case was associated with COVID–19 vaccination. Figure 1 shows different distribution of the cases per year. Of note, we did not observe an increased incidence in the last 3 years and mean age was similar in the years analysed possibly reflecting a limited effect of COVID and COVID–vaccination related incidence in our population.

Diagnostics of ocular mucous membrane pemphigoid

The diagnosis of ocular mucous membrane pemphigoid (MMP) remains achallenge as the timing and choice of diagnostic methods have adecisive influence on its quality. Asystematic approach is required that includes acomprehensive medical history, critical evaluation of the clinical findings and targeted laboratory testing. The diagnosis is complicated by the fact that some patients present purely clinically the symptoms of MMP without fulfilling the required immunohistochemical and laboratory criteria. Basically, the diagnosis of ocular MMP is based on three pillars: 1) medical history and clinical findings, 2) positive immunohistological (direct immunofluorescence) tissue sample and 3) specific serological autoantibodies. As the diagnosis of ocular MMP often implies prolonged systemic immunomodulatory treatment in predominantly older patients, the accurate diagnosis and approach are of critical relevance. The aim of this article is to present the recently updated diagnostic procedure.

A RARE CASE OF INTRAOSSEOUS MUCOEPIDERMOID CARCINOMA OF MAXILLA TREATED AT OUR CENTRE.

Occurrence of Primary intraosseous mucoepidermoid carcinoma (PIOC) within the jaw bones from aberrant salivary tissues is extremely rare. Mandible is more commonly affected but occurrence in maxilla is very rare. The origin of mucoepidermoid carcinoma is controversial and debatable. Primary Intraosseous mucoepidermoid carcinoma is frequently misdiagnosed radiographically and clinically as a benign odontogenic tumor or cyst.Primary Intraosseous Mucoepidermoid Carcinoma has distinct and specic radiological and morphological features for its diagnosis. The main modality of treatment is surgery and appropriate patients are offered adjuvant radiotherapy. This paper reports a case of central mucoepidermoid carcinoma of the Maxilla which was presented as complaints of pain and swelling of upper jaw.Then, he was treated with surgery followed by adjuvant treatment as per specimen pathological report. Here, we have used Simultaneous Integrated Boost technique with helical IMRT for Radiotherapy along with concurrent chemotherapy for treatment of revised margins following positive margins status. Central mucoepider Summary: moid carcinoma is a rare entity with highly selective radiological, histological and immunohistochemical criteria with overall around 150 cases reported. Due to rarity of occurrence, consensus guidelines for treatment protocol have not been established. Here we have described a similar case of a 25yrs old male patient that was diagnosed, surgically resected and has completed adjuvant chemo-radiation therapy at our centre

Interobserver Variation in the Assessment of Immunohistochemistry Expression Levels in HER2-Negative Breast Cancer: Can We Improve the Identification of Low Levels of HER2 Expression by Adjusting the Criteria? An International Interobserver Study

The classification of human epidermal growth factor receptor 2 (HER2) expression is optimized to detect HER2-amplified breast cancer (BC). However, novel HER2-targeting agents are also effective for BCs with low levels of HER2. This raises the question whether the current guidelines for HER2 testing are sufficiently reproducible to identify HER2-low BC. The aim of this multicenter international study was to assess the interobserver agreement of specific HER2 immunohistochemistry scores in cases with negative HER2 results (0, 1+, or 2+/in situ hybridization negative) according to the current American Society of Clinical Oncology/College of American Pathologists (ASCO/CAP) guidelines. Furthermore, we evaluated whether the agreement improved by redefining immunohistochemistry (IHC) scoring criteria or by adding fluorescent in situ hybridization (FISH).We conducted a 2-round study of 105 nonamplified BCs. During the first assessment, 16 pathologists used the latest version of the ASCO/CAP guidelines. After a consensus meeting, the same pathologists scored the same digital slides using modified IHC scoring criteria based on the 2007 ASCO/CAP guidelines, and an extra “ultralow” category was added.Overall, the interobserver agreement was limited (4.7% of cases with 100% agreement) in the first round, but this was improved by clustering IHC categories. In the second round, the highest reproducibility was observed when comparing IHC 0 with the ultralow/1+/2+ grouped cluster (74.3% of cases with 100% agreement). The FISH results were not statistically different between HER2-0 and HER2-low cases, regardless of the IHC criteria used.In conclusion, our study suggests that the modified 2007 ASCO/CAP criteria were more reproducible in distinguishing HER2-0 from HER2-low cases than the 2018 ASCO/CAP criteria. However, the reproducibility was still moderate, which was not improved by adding FISH. This could lead to a suboptimal selection of patients eligible for novel HER2-targeting agents. If the threshold between HER2 IHC 0 and 1+ is to be clinically actionable, there is a need for clearer, more reproducible IHC definitions, training, and/or development of more accurate methods to detect this subtle difference in protein expression levels.

Neuroendocrine neoplasms of the breast: diagnostic agreement and impact on outcome

The classification of breast neuroendocrine neoplasms (Br-NENs) was modified many times over the years and is still a matter of discussion. In the present study, we aimed to evaluate the diagnostic reproducibility and impact on patient outcomes of the most recent WHO 2019 edition of breast tumor classification, namely, for neuroendocrine tumors (NETs) and neuroendocrine carcinomas (NECs). This multicentric observational study included 287 breast neoplasms with NE differentiation. The cases were blindly classified by three independent groups of dedicated breast and/or endocrine pathologists following the 2019 guidelines. Diagnostic concordance and clinical impact were assessed. We observed only a moderate overall diagnostic agreement across the three centers (Cohen’s kappa 0.4532) in distinguishing NET from solid papillary carcinomas (SPCs) and no special type carcinomas (NST) with NE differentiation. Br-NENs were diagnosed in 122/287 (42.5%) cases, subclassified as 11 NET G1 (3.8%), 84 NET G2 (29.3%), and 27 NEC (9.4%), the latter group consisting of 26 large-cell and 1 small-cell NECs. The remaining 165/287 (57.5%) cases were labeled as non-NEN, including SPC, mucinous, NST, and mixed NE carcinomas. While NET and non-NEN cases had a comparable outcome, the diagnosis of NECs showed negative impact on disease-free interval compared to NETs and non-NENs (p = 0.0109). In conclusion, the current diagnostic classification of Br-NENs needs further adjustments regarding morphological and immunohistochemical criteria to increase the diagnostic reproducibility among pathologists. Our data suggest that, apart from high-grade small- and large-cell NECs, Br-NENs behave like non-NEN breast carcinomas and should be managed similarly.

Severe myocarditis as a cause of the formation of cardiorenal syndrome in a patient with refractory rheumatoid arthritis

According to modern concepts, myocarditis is an inflammatory disease of the myocardium, diagnosed on the basis of generally accepted histological, immunological, immunohistochemical criteria. Previously, most researchers believed that the most common cardiac extra-articular manifestation of rheumatoid arthritis (RA) is pericarditis. In the last decade, using magnetic resonance imaging (MRI) of the heart, it turned out that myocarditis in patients with rheumatoid arthritis is not a rare manifestation of the disease. Recently, there is increasing evidence that inflammatory cytokines in RA can also directly cause chronic myocardial damage, further contributing to the development of chronic heart failure (CHF). In our clinical case, myocarditis developed in a patient with active refractory rheumatoid arthritis. The myocardial lesion in the patient was characterized by pronounced echocardiographic signs of restrictive cardiomyopathy, a significant decrease in the ejection fraction with the development of heart failure, various rhythm disturbances in combination with acute renal dysfunction, which led to the formation of cardiorenal syndrome (CRS). Complete regression of myocarditis and cattle occurred precisely against the background of effective treatment of refractory rheumatoid arthritis (RA) with basic antirheumatic drugs and the successful use of biological therapy.

HER2 overexpression/amplification status in colorectal cancer: a comparison between immunohistochemistry and fluorescence in situ hybridization using five different immunohistochemical scoring criteria

ObjectiveAlthough HER2 has gradually become an important therapeutic target for colorectal cancer (CRC), a unified and standard HER2 scoring system was still not established in CRC, and the debatable results of immunohistochemistry and fluorescence in situ hybridization (FISH) in CRC requires further exploration.MethodsIn this study, we use five immunohistochemical (IHC) scoring criteria (i.e., IRS-p, IRS-m, GEA-s, GEA-b and HERACLES) and two FISH criteria to evaluate HER2 status, and further evaluate the correlation between HER2 status and clinicopathological features, survival in a large, unselected Chinese cohort of 664 CRCs.ResultsFinally, we set HER2/CEP17 ratio ≥ 2.0, or an average HER2 copy number ≥ 6.0 as FISH-positive threshold and the amplification rate of HER2 gene was 7.08% (47/664).The HER2 positivity (IHC 3+) was 2.71%, 3.16%, 2.56%, 2.71% and 3.16%, according to the IHC scoring criteria of IRS-p, IRS-m, GEA-s, GEA-b and HERACLES, respectively. Set FISH results as the golden standard; receiver-operating characteristic analysis showed that IRS-p had both high sensitivity and specificity than other IHC scoring systems to evaluate HER2 status. Based on IRS-p criterion, There were significant differences in tumor differentiation (p = 0.038), lymphatic vascular invasion (p = 0.001), pN stage (p value = 0.043), and overall survival (p < 0.001) among IHC score 0–3 + groups. Meanwhile, there were significant differences in pT stage (p = 0.031), pN stage (p = 0.009) and overall survival (p < 0.001) among FISH subgroups.ConclusionThe IRS-p criterion was more suitable for assessing the HER2 status in CRC patients than other IHC criteria. Whereas for FISH scoring system, only HER2/CEP17 < 2.0, meanwhile HER2cn < 4.0 and HER2cn ≥ 6.0 were subgroups with unique clinicopathological characteristics.

Multisystem Langerhans cell histiocystosis in a geriatric patient: case report

&lt;p class="abstract"&gt;Langerhans cell histiocytosis is a condition of exceptional onset characterized by a proliferative event of dendritic cells with mono or multisystem involvement that predominates in the pediatric population and is identified in a smaller proportion in adults. It has a clinical impact and variable prognosis according to its location and number of organs affected. A 68-year-old male patient with clinical and immunohistochemical criteria for Langerhans cell histiocytosis with multisystem settlement with fatal outcome. It is a very rare disease, it is not exclusive to the pediatric population, with little understood pathogenesis and does not have specific treatment. In adults, the clinical impact is more aggressive, with a poorer prognosis and greater short-term complications.&lt;/p&gt;