Validating the Baveno Elastography Criteria of Advanced Liver Fibrosis in Two-Dimensional Shear Wave Elastography: A Prospective Pathology-Based Study.

INTRODUCTION: The Baveno criteria for assessing advanced liver fibrosis were mainly determined by transient elastography (TE), and its pathology-based validation studies in two-dimensional shear wave elastography (2D-SWE) remain limited. We aimed to validate the Baveno criteria through use of 2D-SWE. METHOD: Consecutive patients who underwent liver biopsies for various benign liver diseases were prospectively recruited. Liver stiffness measurement (LSM) was simultaneously evaluated by TE and 2D-SWE. The optimal cutoff value to predict advanced liver fibrosis was determined by the Youden Index, and the diagnostic performance was estimated using area under the receiver operating characteristic (AUROC) analysis. RESULTS: A total of 101 patients were enrolled having a median age of 55.0 (IQR: 46.0-63.5) years, with 53 (52.48%) of them being male. Using <9 and >14 kPa as the optimal dual cutoffs, the AUROC values in TE and 2D-SWE were 0.92 (95% CI: 0.83-0.97) and 0.93 (95% CI: 0.84-0.98), respectively (p = 0.61). The sensitivity and specificity of LSM by TE/2D-SWE achieved rates of 94.44%/94.44% and 86.00%/88.00%, respectively. However, using the Baveno criteria, the AUROC values in TE and 2D-SWE could remain achieving 0.91 (95% CI: 0.82-0.97) and 0.93 (95% CI: 0.84-0.98), respectively (p = 0.36). The sensitivity and specificity in TE/2D-SWE were 88.24%/88.24% and 86.79%/90.57%, respectively. CONCLUSION: This study establishes the compatibility of the Baveno dual cutoff criteria with 2D-SWE, positioning it as an easily used criteria in clinical practice and research.

Rosai-Dorfman disease mimicking craniopharyngioma: a challenging differential diagnosis. Illustrative case.

BACKGROUND: Rosai-Dorfman disease (RDD) is a rare non-Langerhans histiocytic disorder with less than 5% central nervous system involvement and is often mistaken for meningioma given the similarity in imaging features. The authors present the unique case of a 44-year-old female who presented with ongoing visual impairment. OBSERVATIONS: A purely suprasellar mass was noted on magnetic resonance imaging and was initially diagnosed as craniopharyngioma. Unexpectedly, the pathology report revealed RDD. LESSONS: To date, only six cases of sellar RDD have been reported, and our case is the first reported with a purely suprasellar presentation. No standard treatment has been established for RDD, and next-generation sequencing may be a promising therapeutic option.

Lymph Nodes With Increased IgG4-positive Plasma Cells and Patterns Suspicious for IgG4-related Disease: Can Lymph Nodes Be the Only Site of Disease?

Lymphadenopathy with increased immunoglobulin (Ig) G4 + plasma cells can be a nonspecific finding or a manifestation of immunoglobulin G4-related disease (IgG4-RD). It remains unclear whether there are characteristic pathologic features of IgG4-RD involving lymph nodes, or if IgG4-RD lymphadenopathy can occur without other manifestations of IgG4-RD. In this study, we assessed 55 lymph node biopsy specimens (44 men and 11 women with a mean age of 55 y) with increased IgG4 + plasma cells that had 1 of the 6 well-described pathologic patterns. We also correlated these findings with IgG4 serum levels and followed these patients for 7 to 108 months (mean, 34.9 mo) for the occurrence of extranodal IgG4-RD. We further compared lymphadenopathy in patients who developed other manifestations of IgG4-RD (RD + , n=20, 36%) versus those who did not (RD - , n=35, 64%). We found that there were only minor significant differences between 2 groups, including frequency of receiving treatment (RD + , 90% vs. RD - , 60%, P =0.021) and higher serum levels of C-reactive protein (>8 mg/L, RD + , 53% vs. RD - , 13%, P =0.007). Other differences were either borderline or not significant, including mean age (RD + , 59.8 y vs. RD - , 51.9 y, P =0.097), male-to-female ratio (RD + , 16:4 vs. RD - , 28:7, P =1), constitutional symptoms (RD + , 25% vs. RD - , 9%, P =0.096), multiple enlarged lymph nodes (RD + , 45% vs. RD - , 26%, P =0.143), good response to therapy (RD + , 94% vs. RD - , 94%, P =1); higher serum IgG4 levels (>280 mg/dL, RD + , 75% vs. RD - , 51%, P =0.086), anemia (RD + , 45% vs. RD - , 43%, P =0.877), leukopenia (RD + , 0% vs. RD - , 3%, P =0.446), thrombocytopenia (RD + , 10% vs. RD - , 6%, P =0.556), positivity for antinuclear antibody (RD + , 24% vs. RD - , 29%, P =0.688), elevated serum levels of lactate dehydrogenase (>225 U/L, RD + , 0% vs. RD - , 20%, P =0.064), elevated serum IgE level (>100 IU/mL, RD + , 75% vs. RD - , 92%, P =0.238), and hypergammaglobulinemia (RD + , 90% vs. RD - , 86%, P =0.754). There were also no differences in morphologic patterns ( P =0.466), IgG4 + cell location ( P =0.104), eosinophil counts (RD + , 10.3±11.3 vs. RD - , 13.4±17.5, P =0.496), Epstein-Barr virus positivity (RD + , 35% vs. RD - , 60%, P =0.074), and Epstein-Barr virus-positive cell location ( P =0.351). Our findings suggest that there are minimal differences between stringently defined IgG4-RD lymphadenopathy with versus without other manifestations of IgG4-RD. These findings also suggest the existence of IgG4-RD lymphadenopathy as the sole presentation of IgG4-RD.

Clinical Features and Immunophenotypes of Double-Hit Diffuse Large B-Cell Lymphoma.

Double-hit (DH) genetics induces a reduction in the complete remission (CR) and, consequently, in poor overall survival (OS) in diffuse large B-cell lymphoma (DLBCL) patients. Unfortunately, DH identification is time-consuming. Here, we retrospectively reviewed 92 newly diagnosed DLBCL patients, stratified them into the DH (n = 14) and non-DH groups (n = 78), and compared their clinical features and outcomes. The results revealed that the DH group had a higher percentage of bulky disease than the non-DH group (64.3% vs. 28.2%; p = 0.013). More patients in the DH group tested positive for double expresser (DE) (50.0% vs. 21.8%; p = 0.044). The three-year OS rates of patients with and without DH were 33.3% and 52.2%, respectively (p = 0.016). Importantly, advance stage and multiple comorbidities were correlated with a high mortality rate in multivariate analysis. Furthermore, by combining DE and the bulky disease, a specificity of 89.7% for DH prediction was achieved. In summary, DH genetics, not DE immunopositivity, could be a factor for an inferior OS in DLBCL. A combination of bulky disease and a positive DE immunophenotype could facilitate DH genetics prediction in newly diagnosed DLBCL patients.

Targeted Next-generation Sequencing Reveals a Wide Morphologic and Immunophenotypic Spectrum of Monomorphic Epitheliotropic Intestinal T-Cell Lymphoma.

Primary intestinal T-cell lymphoma (PITL) is highly aggressive and includes celiac disease-related enteropathy-associated T-cell lymphoma (EATL), monomorphic epitheliotropic intestinal T-cell lymphoma (MEITL), and primary intestinal peripheral T-cell lymphoma, not otherwise specified (ITCL-NOS). MEITL is the most common PITL in Asia, comprising of monomorphic medium-sized cells typically expressing CD8, CD56, and cytotoxic granules. Occasional cases with intermediate features between MEITL and ITCL-NOS are difficult to be classified and warrant further investigation. We collected 54 surgically resected PITLs from Taiwan, with 80% presenting with bowel perforation. The overall outcome was poor with a median survival of 7 months. Based on histopathology (monomorphic vs. pleomorphic) and immunophenotype, we classified these cases into 4 groups: MEITL with typical immunophenotype (n=34), MEITL with atypical immunophenotype (n=5), pleomorphic PITL with MEITL-like immunophenotype (n=6), and ITCL-NOS (n=9). There was no EATL in our cohort. Targeted next-generation sequencing of the first 3 groups showed highly prevalent loss-of-function mutations for SETD2 (85%, 80%, and 83%, respectively) and frequent activating mutations for STAT5B (64%, 60%, and 50%, respectively) and JAK3 (38%, 20%, and 50%, respectively). In contrast, ITCL-NOS cases had less frequent mutations of SETD2 (56%) and STAT5B (11%) and rare JAK3 mutations (11%). Our results suggest that there is a wider morphologic and immunophenotypic spectrum of MEITL as currently defined in the 2017 WHO classification. MEITL with atypical immunophenotype and PITL with MEITL-like immunophenotype shared clinicopathologic and molecular features similar to MEITL but distinct from ITCL-NOS, indicating that such cases may be considered as immunophenotypic or histopathologic variants of MEITL.

Clinicopathologic Features of Lymphoproliferative Neoplasms Involving the Liver.

Background and Objectives: Primary hepatic lymphoproliferative neoplasms (PHL) are uncommon. This retrospective study is aimed to present the clinicopathological characteristics of PHL and compare to secondary hepatic lymphoproliferative neoplasms (SHL). Materials and Methods: Patients who were diagnosed with lymphoproliferative neoplasms involving the liver between January 2004 and December 2018 at a tertiary medical center in central Taiwan were included. The demographic and clinical data, radiological results and histopathological findings were reviewed and summarized. Results: We analyzed 36 patients comprising 6 PHL patients and 30 SHL patients. The median age at diagnosis tended to be younger in PHL than in SHL (59 vs. 63 years old, p = 0.349). Both entities had a small male predominance. The PHL patients tended to have higher levels of aspartate aminotransferase, alanine transaminase and serum albumin and lower levels of alkaline phosphatase, total bilirubin, γ-glutamyl transferase and lactate dehydrogenase compared with SHL, but there was no significant difference. Multiple mass lesions were the most common radiological finding in both groups. Diffuse large B-cell lymphoma was the predominant subtype in both groups (67% in PHL and 40% in SHL). The PHL patients had a longer median survival than the SHL patients (not reached vs. 3 months, p = 0.003). Conclusions: Although there was no significant difference between PHL and SHL in clinical, laboratory and radiological features, the SHL patients had very poor outcomes with a median survival time of 3 months. Effective therapies are urgently required for these patients.

Investigating early progression of Hodgkin lymphoma in a two-center analysis.

BACKGROUND/PURPOSE: The early progression of disease (POD) of Hodgkin lymphoma (HL) leads to a poor prognosis. To identify risk factors for early POD, this retrospective two-center cohort analysis was conducted. METHODS: Medical records of HL patients between 1998 and 2020 from two referral centers were reviewed. RESULTS: Two-hundred and sixty-nine patients were analyzed. The distribution of early vs. advanced stages was 51.1 vs. 48.9%, respectively. The 5-year progression free survival (PFS) was 63%, and the overall survival (OS) was 87% with a median follow-up of 52.0 months. The complete remission (CR) rate was 85.7%. Disease progression or relapsed disease occurred in 33.9% (n = 85) of patients while 17.0% of this cohort had early POD within 12 months of induction therapy. Patients with early POD had a worse median OS than those without (p < 0.001). Failure to achieve post-induction CR and high international prognostic score (IPS, 3-7) were independent risk factors for early POD. Compared with chemotherapy alone, consolidative radiotherapy after induction chemotherapy was associated with a lower risk of early POD (21.3% vs. 6.2%, p = 0.006). CONCLUSION: High IPS was an independent risk factor for early POD, which was less observed in those with consolidative radiotherapy.

Machine Learning Based on Morphological Features Enables Classification of Primary Intestinal T-Cell Lymphomas.

The aim of this study was to investigate the feasibility of using machine learning techniques based on morphological features in classifying two subtypes of primary intestinal T-cell lymphomas (PITLs) defined according to the WHO criteria: monomorphic epitheliotropic intestinal T-cell lymphoma (MEITL) versus intestinal T-cell lymphoma, not otherwise specified (ITCL-NOS), which is considered a major challenge for pathological diagnosis. A total of 40 histopathological whole-slide images (WSIs) from 40 surgically resected PITL cases were used as the dataset for model training and testing. A deep neural network was trained to detect and segment the nuclei of lymphocytes. Quantitative nuclear morphometrics were further computed from these predicted contours. A decision-tree-based machine learning algorithm, XGBoost, was then trained to classify PITL cases into two disease subtypes using these nuclear morphometric features. The deep neural network achieved an average precision of 0.881 in the cell segmentation work. In terms of classifying MEITL versus ITCL-NOS, the XGBoost model achieved an area under receiver operating characteristic curve (AUC) of 0.966. Our research demonstrated an accurate, human-interpretable approach to using machine learning algorithms for reducing the high dimensionality of image features and classifying T cell lymphomas that present challenges in morphologic diagnosis. The quantitative nuclear morphometric features may lead to further discoveries concerning the relationship between cellular phenotype and disease status.

Morphologic Spectrum of Lymphadenopathy in Adult-onset Immunodeficiency (Anti-interferon-γ Autoantibodies).

Adult-onset immunodeficiency syndrome (AOIS) caused by anti-interferon-γ autoantibodies is an emerging disease. Affected patients present typically with systemic lymphadenopathy, fatigue, and fever. We studied 36 biopsy specimens, 31 lymph nodes, and 5 extranodal sites, of AOIS confirmed by serum autoantibody or QuantiFERON-TB Gold In-Tube assay. We describe the morphologic features and the results of ancillary studies, including special stains, immunohistochemistry, and molecular testing. The overall median age of these patients was 60.5 years (range, 41 to 83 y) with a male-to-female ratio of 20:16. All biopsy specimens showed nontuberculous mycobacterial infection, and most cases showed the following histologic features: capsular thickening with intranodal sclerosing fibrosis, irregularly distributed ill-formed granulomas or histiocytic aggregates with neutrophilic infiltration, interfollicular expansion by a polymorphic infiltrate with some Hodgkin-like cells that commonly effaces most of the nodal architecture and proliferation of high endothelial venules. In situ hybridization analysis for Epstein-Barr virus-encoded RNA showed scattered (<1%) to relatively more common (4% to 5%) positive cells in 29 of 30 (97%) tested specimens, reflecting immune dysregulation due to an interferon-γ defect. In the 31 lymph node specimens, 23 (74%) cases showed increased immunoglobulin G4-positive plasma cells (4 to 145/HPF; mean, 49.7/HPF) with focal areas of sclerosis reminiscent of immunoglobulin G4-related lymphadenopathy, 4 (13%) cases resembled, in part, nodular sclerosis Hodgkin lymphoma, and 9 (29%) cases mimicked T-cell lymphoma. Among 33 patients with available clinical follow-up, 20 (61%) showed persistent or refractory disease despite antimycobacterial therapy, and 1 patient died of the disease. We conclude that the presence of ill-defined granulomas, clusters of neutrophils adjacent to the histiocytic aggregates, and some Epstein-Barr virus-positive cells are features highly suggestive of AOIS. A high index of clinical suspicion and awareness of the morphologic features and differential diagnosis of AOIS are helpful for establishing the diagnosis.

Granuloma With an Underlying Lymphoma: A Diagnostic Challenge and a Wider Histologic Spectrum Including Adult T-Cell Leukemia/Lymphoma.

Granulomatous reaction is not uncommon in histopathology, with various etiologies in different organs and geographic regions. Lymphoma is one of the underlying causes of granuloma; and sometimes the neoplastic cells may be masked by the granulomatous reaction. In this report, we present our experience with 7 lymphoma cases of various histologic types with coexisting granuloma to show the diagnostic challenges. In all cases, a granulomatous reaction was simultaneously present with the neoplastic cells. The 7 cases included 3 cases of adult T-cell leukemia/lymphoma in the lymph node or skin including one coexisting with mycobacterial infection, 2 cases of classical Hodgkin lymphoma involving the liver, and 1 case each of systemic Epstein-Barr virus-positive peripheral T-cell lymphoma and a hepatic inflammatory pseudotumor-like follicular dendritic cell sarcoma. Three cases were initially misdiagnosed as reactive change or mycobacterial infection instead of lymphoma, and a wrong histologic lymphoma type was diagnosed in 1 case. In this report, we showed that granulomatous reaction might mask lymphomas of various histologic types; and a diagnosis of mycobacterial infection or sarcoidosis could not exclude the possibility of an underlying lymphoma. We emphasized the importance of detailed histologic examination with the aid of ancillary studies to reach a correct diagnosis and to avoid inappropriate management of the patients. Our study also broadened the spectrum of lymphoma types coexisting with granuloma.

Renal actinomycosis with retroperitoneal abscess in a cirrhotic patient: A case report (CARE-complaint).

RATIONALE: Renal actinomycosis is a rare clinical infection, subacute to chronic presentation caused by the Actinomyces bacteria. Actinomyces israelii is diagnosed in the overpowering majority of reported cases. Abdominopelvic manifestation forms 10% to 20% of all actinomycosis, and may be misdiagnosed as either a malignancy or chronic inflammation due to the lower correct preoperative diagnostic rate (<10%). PATIENT CONCERNS: A 38-year-old man with alcoholic liver cirrhosis experienced right flank pain, abdominal pain, and fever for 3 days. Leukocytosis, acute kidney injury, and impaired liver function were found. A computed tomographic scan demonstrated multiple renal cystic lesions, along with fluid accumulation at the right subphrenic and retroperitoneal spaces. DIAGNOSES: Renal actinomycosis was confirmed via cultures of both the abscess and nephrectomy specimen which grew A israelii and the pathological findings of multiple renal abscesses of actinomycosis with the characteristics of sulfur granules. INTERVENTIONS: A nephrectomy was performed for an inadequate percutaneous drainage of renal abscess. OUTCOMES: A full course of antibiotics with intravenous penicillin G (3 million units every 4 hours) was prescribed for 2 weeks, followed by oral penicillin V given at a dose of 2 grams per day for 6 months at our out-patient facility. LESSONS: A precise diagnosis of primary renal actinomycosis depends on any histopathological findings and/or cultures of specimens. A high dose of intravenous penicillin G is the first choice, followed by oral penicillin V, with the duration of each being dependent upon the individual condition.

Prognostic Significance of the Dynamic Change of Programmed Death-ligand 1 Expression in Patients with Multiple Myeloma.

Background The inhibition of programmed cell death protein 1/programmed death-ligand 1 (PD-1/PD-L1) signaling pathway has been shown to be an effective targeted therapy in fighting both solid organ cancers and hematological malignancies. PD-L1 expression also serves as a prognostic marker in various cancers. However, the expression of PD-L1 and its prognostic significance in multiple myeloma remains largely unknown. Methods Immunohistochemistry staining of PD-L1 was performed in bone marrow biopsy samples (total of 85 samples) in 32 myeloma patients receiving autologous stem cell transplant (ASCT) at various time points: before ASCT, post-ASCT, and/or at relapse after ASCT. More than 1% of myeloma cells with PD-L1 staining was considered a positive expression of PD-L1. A correlation analysis was performed between post-ASCT overall survival (OS) and the status of PD-L1 expression. Results In this pilot study, a total of 11 patients (34%) out of our cohort (32 patients) were positive for PD-L1 expression at least once during the course of the disease. A dynamic change of PD-L1 expression was noted in three patients converting from negative (before ASCT) to positive (post-ASCT) and two patients converting from positive (before ASCT) to negative (post-ASCT). Patients with positive PD-L1 expression persisting or occurring post-ASCT had shorter post-ASCT overall survival than those with negative PD-L1 expression post-ASCT (median survival: 13 vs 23 months, p<0.05). No significant differences were detected in the known prognostic factors between these two groups at the time of ASCT. Pre-transplant PD-L1 expression status, however, showed no significant impact on post-ASCT overall survival. Furthermore, a few patients switching from positive PD-L1 expression before ASCT to negative PD-L1 expression post-ASCT had a relatively good post-ASCT overall survival (n=2, overall survival of 29 and 56 months, respectively). Conclusion Immunohistochemistry can be reliably used for measuring PD-L1 expression in decalcified marrow core biopsy materials. Our results suggest that positive PD-L1 expression persisting/occurring post-ASCT could be an adverse prognostic marker for post-ASCT OS. Additionally, PD-L1 expression appears to be dynamic and is subjected to change after ASCT. Our findings suggest that periodically monitoring PD-L1 expression in patients with multiple myeloma post-ASCT is warranted. Further studies are needed to confirm our initial observation and to evaluate if timely intervention with PD-L1 blockade can improve post-ASCT outcomes in myeloma patients.

Primary gastrointestinal anaplastic large cell lymphoma.

Primary gastrointestinal anaplastic large cell lymphoma (GI-ALCL) is rare. We report eight new cases. The median age was 61.5 years (range 10-88), most frequently involving the stomach (n = 3) and small intestine (n = 4). The neoplastic hallmark cells in all cases expressed CD30. Anaplastic lymphoma kinase (ALK) protein was expressed in two cases (25%). By in situ hybridisation, all cases were negative for Epstein-Barr virus and for DUSP22/IRF4 gene translocation. At a median follow-up time of 37.5 months, four patients died of disease, one was alive with disease, and three were disease-free. Our literature review showed that GI-ALCL occurred mainly in older patients and was characterised by a low rate of ALK expression, a high rate of T-cell lineage, and a frequent occurrence in the small intestine. Incorporating our two ALK+ GI-ALCL cases together with the four cases in the literature, the median age was 34 years (range 10-56), with four (67%) cases in the small intestine. The six patients were all alive with a median follow-up of 21 months. The 5-year overall survival of our six patients with ALK- GI-ALCL was 40%, in contrast to 100% with ALK+ GI-ALCL. The prognosis for ALK- GI-ALCL was poor, while that for the ALK+ counterparts was good.

Polyclonality in Sclerosing Angiomatoid Nodular Transformation of the Spleen.

Sclerosing angiomatoid nodular transformation (SANT) of the spleen is a morphologically distinctive lesion. Although the clinical course of SANT is benign, its reactive or neoplastic nature remains to be clarified. Furthermore, some investigators have suggested that SANT is related to IgG4 sclerosing lesion or inflammatory pseudotumor with stromal cells positive for Epstein-Barr virus (EBV). In this study, we assessed 22 cases of SANT derived from adult women. Clinical data and follow-up information were obtained by chart review. Immunohistochemical studies for IgG4, IgG, and CD21 stains and in situ hybridization to detect EBV-encoded small RNAs were performed. We also assessed genomic DNA extracted from paraffin-embedded tissue for human androgen-receptor α gene analysis using conventional and methylation-specific polymerase chain reaction methods. The median patient age was 41.5 years (range, 25 to 82 y). Most (77%) patients presented with a single mass that was detected incidentally (59%). The mean size of the lesions was 3.8 cm (range, 1.0 to 9.0 cm). Clinical symptoms correlated with multiple lesions (P=0.043) but not lesional size (P=0.637) or location in the spleen (hilum vs. periphery, P=0.696). None of the cases had evidence of IgG4-related disease or recurred after splenectomy. The mean number of IgG4 cells was 27.7 (range, 4 to 125), and the mean IgG4/IgG ratio was 16.4% (range, 1.6% to 55.7%) with only 2 cases being >40%. Cases with higher IgG4 cells did not correlate with inflammatory pseudotumor-like morphology. No lesions were positive for EBV-encoded small RNAs, and almost all cases with informative results (n=19) showed a polyclonal pattern. We conclude that SANT is a polyclonal, reactive lesion rather than a neoplasm.