Frontline therapy with bendamustine rituximab (BR) and rituximab cyclophosphamide vincristine prednisone (RCVP) confers similar long-term outcomes in patients with treatment naïve Waldenström macroglobulinemia in a real-world setting: a population-based analysis.

We report on outcomes of 111 patients with treatment naïve Waldenström macroglobulinemia (TN WM) treated with frontline bendamustine-rituximab (BR) (n = 57) or rituximab-cyclophosphamide-vincristine-prednisone (RCVP) (n = 54). Median follow-up was 60.7 months (range 1.9-231.6). Median progression-free survival (PFS) was 60.5 months (95% CI 47.6-73.4) for BR and 79.0 months (95% CI 31.3-126.8) for RCVP (p = .96). Median overall survival (OS) was not reached for BR and 153.4 months (95% CI 114.5-192.4) for RCVP (p = .37). While overall and major response rates did not differ between treatment groups, BR had numerically higher rate of very good partial response or better response (51% vs. 37%, p = .30) and complete response (26% vs. 13%, p = .13). RCVP confers comparable outcomes to BR in a real-world population of TN WM patients and remains an effective regimen, particularly when tolerance or frailty is an issue, or in resource-limited settings.

Kikuchi-Fujimoto Disease Following COVID-19 Vaccination: Experience at a Population-Based Referral Center.

OBJECTIVES: Multiple case reports describe Kikuchi-Fujimoto disease (KFD) following COVID-19 vaccination, but the true nature of this phenomenon is unknown. The purpose of this study was to further assess the relationship between KFD and COVID-19 vaccination at the population level. METHODS: Confirmed KFD cases from January 2018 to April 2022 were identified from provincial pathology archives and analyzed in the context of vaccination statistics from public health resources. RESULTS: Our statistical models provide evidence of a temporal association between KFD and both antecedent COVID-19 vaccine administration as well as age-stratified vaccination rates. Eight new cases of plausible COVID-19 vaccine-associated KFD are presented, collectively exhibiting clinical and pathologic features that overlap substantially with those of idiopathic KFD. CONCLUSIONS: Our findings indicate that KFD is observed in association with COVID-19 vaccination and suggest that mechanistic studies are warranted.

The outcome of older adults with classic Hodgkin lymphoma in British Columbia.

Outcomes in older adults with classic Hodgkin lymphoma (cHL) have traditionally been poor, in part, related to poor tolerance to standard chemotherapy. Herein, we evaluated the survival of patients with cHL aged ≥60 years in British Columbia in a population-based analysis. From 1961 to 2019, 744 patients with newly diagnosed cHL were identified. With a median follow-up of 9 years, 5-year disease-specific survival (DSS) and overall survival (OS) have improved by decade comparison (both P < .001), remaining stable in the past 20 years (DSS, P = .35; OS, P = .26). In the modern management era (2000-present), 361 of 401 patients (90%) received active therapy for cHL and had a 5-year OS of 60%. For those who received curative-intent therapy (n = 327), the 5-year progression-free survival (PFS), OS, and DSS were 60%, 65%, and 76%, respectively, and estimates were superior in those who were 60 to 69 years of age (72%, 77%, and 83%, respectively) compared with those who were 70 to 79 years of age (54%, 57%, and 70%, respectively) and ≥80 years of age (28%, 39%, and 63%, respectively) (P < .05 for all). Overall, pulmonary toxicity occurred in 58 of 279 patients (21%) treated with bleomycin, with 22 of 58 (38%) occurring after cycles 1 or 2, accounting for 8 of 20 (40%) treatment-related deaths. Outcomes in older adults with cHL have improved in recent decades; however, they remain poor for those aged ≥70 years, even in the modern treatment era. Furthermore, treatment-related toxicity remains a significant concern and use of bleomycin should be avoided in most patients.

The impact of whole genome and transcriptome analysis (WGTA) on predictive biomarker discovery and diagnostic accuracy of advanced malignancies.

In this study, we evaluate the impact of whole genome and transcriptome analysis (WGTA) on predictive molecular profiling and histologic diagnosis in a cohort of advanced malignancies. WGTA was used to generate reports including molecular alterations and site/tissue of origin prediction. Two reviewers analyzed genomic reports, clinical history, and tumor pathology. We used National Comprehensive Cancer Network (NCCN) consensus guidelines, Food and Drug Administration (FDA) approvals, and provincially reimbursed treatments to define genomic biomarkers associated with approved targeted therapeutic options (TTOs). Tumor tissue/site of origin was reassessed for most cases using genomic analysis, including a machine learning algorithm (Supervised Cancer Origin Prediction Using Expression [SCOPE]) trained on The Cancer Genome Atlas data. WGTA was performed on 652 cases, including a range of primary tumor types/tumor sites and 15 malignant tumors of uncertain histogenesis (MTUH). At the time WGTA was performed, alterations associated with an approved TTO were identified in 39 (6%) cases; 3 of these were not identified through routine pathology workup. In seven (1%) cases, the pathology workup either failed, was not performed, or gave a different result from the WGTA. Approved TTOs identified by WGTA increased to 103 (16%) when applying 2021 guidelines. The histopathologic diagnosis was reviewed in 389 cases and agreed with the diagnostic consensus after WGTA in 94% of non-MTUH cases (n = 374). The remainder included situations where the morphologic diagnosis was changed based on WGTA and clinical data (0.5%), or where the WGTA was non-contributory (5%). The 15 MTUH were all diagnosed as specific tumor types by WGTA. Tumor board reviews including WGTA agreed with almost all initial predictive molecular profile and histopathologic diagnoses. WGTA was a powerful tool to assign site/tissue of origin in MTUH. Current efforts focus on improving therapeutic predictive power and decreasing cost to enhance use of WGTA data as a routine clinical test.

Outcome of limited-stage nodular lymphocyte-predominant Hodgkin lymphoma and the impact of a PET-adapted approach.

Radiotherapy (RT) is typically incorporated into the treatment of limited-stage nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL), although it remains unknown whether chemotherapy alone may be suitable in select patients. We evaluated outcomes of limited-stage NLPHL at BC Cancer on the basis of era-specific guidelines: routine RT era, 1995 to 2005 (n = 36), combined modality with 2 cycles of doxorubicin, bleomycin, vinblastine, dacarbazine (ABVD) chemotherapy followed by RT or RT alone; positron emission tomography (PET) era, after 2005 (n = 63), ABVD alone (4 cycles) if the PET scan after the second cycle of ABVD (PET2) is negative, or treatment is changed to RT if PET2 is positive. Median age of patients was 38 years (range, 16-82 years), 73% were male, and 43% had stage II. With a median follow-up of 10.5 years for all patients, 5-year progression-free survival (PFS) was 91% [corrected] and was 97% for overall survival (OS), with no difference by treatment era (PFS, P = .15; [corrected] OS, P = .35). For the 49 patients who had a PET2 scan, 86% were PET negative and 14% were PET positive by Deauville criteria with 5-year PFS rates of 92% and 80% (P = .87) [corrected], respectively. This is the largest study of a PET-adapted approach in NLPHL and supports that ABVD alone may be a viable option in select patients with a negative PET2 scan, with consideration of acute and long-term toxicities.

Outcome of relapsed and refractory nodular lymphocyte-predominant Hodgkin lymphoma: a North American analysis.

Nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL) is a rare entity, with limited data on the outcome in the relapsed/refractory setting. We evaluated the outcome of all patients diagnosed between 04/1979 and 01/2019 with relapsed or progressive NLPHL after initial active therapy at two institutions, refractory disease being defined as lack of response to treatment and/or relapse within three months of treatment. NLPHL patients with histological evidence of transformation at time of first relapse or progression were excluded. In total, 69 patients with recurrent NLPHL were included in the study. After a median follow-up after initial diagnosis of 14 years (range, 0·5-46 years), median progression-free survival after front-line treatment (PFS-1) was four years. Second-line therapy included chemotherapy in 28 (41%) patients, biological therapy (rituximab, lenalidomide or brentuximab vedotin) in 14 (20%), high-dose chemotherapy followed by autologous stem cell transplant in 14 (20%) and radiation therapy (RT) alone in 10 (15%). The five-year PFS after second-line therapy (PFS-2) was 68% [95% confidence interval (CI), 54-79%] but the five-year overall survival (OS) after second-line therapy (OS-2) remained excellent, at 94% (95% CI, 85-99%). Due to excellent outcome in case of recurrence, studies aimed at characterizing its biology to guide therapy de-escalation are needed.

Long-term results of PET-guided radiation in patients with advanced-stage diffuse large B-cell lymphoma treated with R-CHOP.

Consolidative radiation therapy (RT) for advanced-stage diffuse large B-cell lymphoma (DLBCL) remains controversial, with routine practice continuing to include RT in patients with initial bulky disease or residual masses. Positron emission tomography (PET)-computed tomography is a sensitive modality for detecting the presence of residual disease at the end of treatment (EOT). A PET-guided approach to selectively administering RT has been the policy in British Columbia since 2005. Patients with advanced-stage DLBCL diagnosed from 1 January 2005 to 1 March 2017 and treated with at least 6 cycles of R-CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisolone plus rituximab), who underwent EOT PET, were included in this analysis. Those with complete metabolic response (PET-negative [PET-NEG]) were observed; those with PET-positive (PET-POS) scans were offered consolidative RT, when feasible. Of the patient records reviewed, 723 were identified, with median follow-up of 4.3 years: 517 (72%) were PET-NEG; 206 (28%) were PET-POS. Time to progression (TTP) and overall survival (OS) at 3 years were 83% vs 56% and 87% vs 64%, in patients with PET-NEG and PET-POS scans, respectively. PET-POS patients with nonprogressing disease treated with consolidative RT (109 and 206; 53%) had outcomes approaching those of PET-NEG patients, with 3-year estimates of 76% and 80% for TTP and OS. PET-NEG patients who had bulky disease (≥10 cm) at diagnosis had outcomes indistinguishable from those without bulk, despite the omission of RT. These data suggest that patients with advanced-stage DLBCL who are PET-NEG at EOT and receive no RT have excellent outcomes. 18F-fluorodeoxyglucose-PET can reliably guide selective administration of consolidative RT, even in patients with initially bulky disease.

Outcome of primary mediastinal large B-cell lymphoma using R-CHOP: impact of a PET-adapted approach.

Cure rates for primary mediastinal large B-cell lymphoma (PMBCL) have improved with the integration of rituximab. However, the type of primary therapy and role of radiotherapy (RT) remains ill-defined. Herein, we evaluated the outcome of PMBCL primarily treated with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) and the impact of an end-of-treatment (EOT) 18F-fluorodeoxyglucose positron emission tomography (PET) scan to guide consolidative RT. Patients ≥18 years of age with PMBCL treated with curative intent rituximab-chemotherapy were identified. Prior to 2005, patients were recommended to receive R-CHOP + RT (RT era). Beginning in 2005, EOT PET was used to guide RT and only those with a PET-positive scan received RT (PET era). In total, 159 patients were identified, 94% were treated with R-CHOP and 44% received RT (78% in RT era, 28% in PET era). The 5-year time to progression (TTP) and overall survival (OS) for the entire cohort were 80% and 89%, respectively, similar across treatment eras. Overall, 10% had refractory disease. In total, 113 patients had an EOT PET scan: 63% negative and 37% positive with a 5-year TTP of 90% vs 71% and 5-year OS of 97% vs 88%, respectively. For those with Deauville (D)-scored PET scans (n = 103), the 5-year TTP for PET-negative cases by Deauville criteria (D1-D3, DX) was 91%, with inferior outcomes for D5 vs D4 (5-year TTP 33% vs 87%, P = .0002). Outcomes for PMBCL treated with RCHOP are favorable and use of a PET-adapted approach reduces RT in the majority of patients. A small proportion have refractory disease and may benefit from an alternate treatment.

Ureteral Metastasis From Prostate Cancer: A PSMA PET Pitfall.

A 72-year-old man with a history of prostate adenocarcinoma initially managed by radical prostatectomy and salvage radiation therapy underwent resection of a left vas deferens recurrence identified on PSMA PET. Despite an initial response, PSA failed to fall below 3.5 ng/L, prompting re-evaluation with PSMA PET/CT: a left distal hydroureter with presumed physiologic urine activity remains despite diuretic administration. Upon scrutiny of the prior PSMA PET/CT and diagnostic CTs, the distal ureteral uptake matched a subtle circumferential area of enhancing mild ureteral thickening. Pathological review after left uretectomy confirmed metastatic prostate cancer.

Histiocytosis masquerading in the mesentery and pleura.

We present an atypical presentation of Rosai-Dorfman disease (RDD). Due to its overlap with IgG4-related disease (IgG4-RD), this case proved to be a diagnostic dilemma. Our case is an example of the importance of having a broad-based differential and, ultimately, an in-depth histopathological review. Our patient presented with a constellation of symptoms suggestive of an underlying malignancy. He was provisionally diagnosed with peritoneal carcinomatosis of an unknown primary. His initial presentation triggered a series of investigations, surgery and biopsies. Omental biopsy specimens were suggestive of IgG4-RD. Despite appropriate treatment for IgG4-RD, his disease progressed, specifically in the lungs. Pleural biopsies were then collected and assessed alongside the omental biopsies. On review and reassessment, the patient was formally diagnosed with RDD.

Early progression after bendamustine-rituximab is associated with high risk of transformation in advanced stage follicular lymphoma.

Despite widespread use of bendamustine and rituximab (BR) as frontline therapy for advanced-stage follicular lymphoma (FL), little is known about the risk of early progression or incidence of histological transformation. We performed a retrospective analysis of a population-based cohort of 296 patients with advanced-stage FL treated with frontline BR and maintenance rituximab. As previously demonstrated, outcomes with this regimen are excellent, with 2-year event-free survival estimated at 85% (95% confidence interval [95% CI], 80-89) and 2-year overall survival 92% (95% CI, 88-95). Progression of disease within 24 months (POD24) occurred in 13% of patients and was associated with a significantly inferior outcome with 2-year overall survival of 38% (95% CI, 20-55). The only significant risk factor for POD24 at baseline was elevated lactate dehydrogenase (P < .001). Importantly, the majority of POD24 patients (76%) had transformed disease. Compared with a historical cohort treated with rituximab, cyclophosphamide, vincristine, and prednisone, event-free survival has improved and the risk of POD24 has decreased, but a higher proportion of patients with POD24 harbor transformation. The overall incidence of transformation appears unchanged. The presence of occult or early transformation is the main driver of POD24 in FL patients treated with frontline BR. Identification of biomarkers and improved management strategies for transformation will be crucial to improving outcomes.

Comparison of Artificial Intelligence Techniques to Evaluate Performance of a Classifier for Automatic Grading of Prostate Cancer From Digitized Histopathologic Images.

Importance: Proper evaluation of the performance of artificial intelligence techniques in the analysis of digitized medical images is paramount for the adoption of such techniques by the medical community and regulatory agencies. Objectives: To compare several cross-validation (CV) approaches to evaluate the performance of a classifier for automatic grading of prostate cancer in digitized histopathologic images and compare the performance of the classifier when trained using data from 1 expert and multiple experts. Design, Setting, and Participants: This quality improvement study used tissue microarray data (333 cores) from 231 patients who underwent radical prostatectomy at the Vancouver General Hospital between June 27, 1997, and June 7, 2011. Digitized images of tissue cores were annotated by 6 pathologists for 4 classes (benign and Gleason grades 3, 4, and 5) between December 12, 2016, and October 5, 2017. Patches of 192 µm2 were extracted from these images. There was no overlap between patches. A deep learning classifier based on convolutional neural networks was trained to predict a class label from among the 4 classes (benign and Gleason grades 3, 4, and 5) for each image patch. The classification performance was evaluated in leave-patches-out CV, leave-cores-out CV, and leave-patients-out 20-fold CV. The analysis was performed between November 15, 2018, and January 1, 2019. Main Outcomes and Measures: The classifier performance was evaluated by its accuracy, sensitivity, and specificity in detection of cancer (benign vs cancer) and in low-grade vs high-grade differentiation (Gleason grade 3 vs grades 4-5). The statistical significance analysis was performed using the McNemar test. The agreement level between pathologists and the classifier was quantified using a quadratic-weighted κ statistic. Results: On 333 tissue microarray cores from 231 participants with prostate cancer (mean [SD] age, 63.2 [6.3] years), 20-fold leave-patches-out CV resulted in mean (SD) accuracy of 97.8% (1.2%), sensitivity of 98.5% (1.0%), and specificity of 97.5% (1.2%) for classifying benign patches vs cancerous patches. By contrast, 20-fold leave-patients-out CV resulted in mean (SD) accuracy of 85.8% (4.3%), sensitivity of 86.3% (4.1%), and specificity of 85.5% (7.2%). Similarly, 20-fold leave-cores-out CV resulted in mean (SD) accuracy of 86.7% (3.7%), sensitivity of 87.2% (4.0%), and specificity of 87.7% (5.5%). Results of McNemar tests showed that the leave-patches-out CV accuracy, sensitivity, and specificity were significantly higher than those for both leave-patients-out CV and leave-cores-out CV. Similar results were observed for classifying low-grade cancer vs high-grade cancer. When trained on a single expert, the overall agreement in grading between pathologists and the classifier ranged from 0.38 to 0.58; when trained using the majority vote among all experts, it was 0.60. Conclusions and Relevance: Results of this study suggest that in prostate cancer classification from histopathologic images, patch-wise CV and single-expert training and evaluation may lead to a biased estimation of classifier's performance. To allow reproducibility and facilitate comparison between automatic classification methods, studies in the field should evaluate their performance using patient-based CV and multiexpert data. Some of these conclusions may be generalizable to other histopathologic applications and to other applications of machine learning in medicine.

Automatic grading of prostate cancer in digitized histopathology images: Learning from multiple experts.

Prostate cancer (PCa) is a heterogeneous disease that is manifested in a diverse range of histologic patterns and its grading is therefore associated with an inter-observer variability among pathologists, which may lead to an under- or over-treatment of patients. In this work, we develop a computer aided diagnosis system for automatic grading of PCa in digitized histopathology images using supervised learning methods. Our pipeline comprises extraction of multi-scale features that include glandular, cellular, and image-based features. A number of novel features are proposed based on intra- and inter-nuclei properties; these features are shown to be among the most important ones for classification. We train our classifiers on 333 tissue microarray (TMA) cores that were sampled from 231 radical prostatectomy patients and annotated in detail by six pathologists for different Gleason grades. We also demonstrate the TMA-trained classifier's performance on additional 230 whole-mount slides of 56 patients, independent of the training dataset, by examining the automatic grading on manually marked lesions and randomly sampled 10% of the benign tissue. For the first time, we incorporate a probabilistic approach for supervised learning by multiple experts to account for the inter-observer grading variability. Through cross-validation experiments, the overall grading agreement of the classifier with the pathologists was found to be an unweighted kappa of 0.51, while the overall agreements between each pathologist and the others ranged from 0.45 to 0.62. These results suggest that our classifier's performance is within the inter-observer grading variability levels across the pathologists in our study, which are also consistent with those reported in the literature.

Lymphoproliferative Disorders of the Gastrointestinal Tract.

CONTEXT: - The diagnosis of gastrointestinal lymphoproliferative disorders can be challenging because of the small size of biopsies and the wide spectrum of lymphoproliferative disorders that may be encountered. OBJECTIVE: - To review the spectrum of lymphoproliferative disorders involving the gastrointestinal tract, highlighting potential pitfalls. DATA SOURCES: - Peer-reviewed articles and clinical experience. CONCLUSIONS: - Interpretation of lymphoid infiltrates in gastrointestinal biopsies requires synthesis of morphologic, immunophenotypic, molecular genetic, and clinical information. Knowledge of indolent lymphoproliferative disorders that may mimic aggressive lymphomas will help in preventing misdiagnoses.

IgG4-related disease and lymphocyte-variant hypereosinophilic syndrome: A comparative case series.

OBJECTIVE: To compare the clinical and laboratory features of IgG4-related disease (IgG4-RD) and lymphocyte-variant hypereosinophilic syndrome (L-HES), two rare diseases that often present with lymphadenopathy, gastrointestinal symptoms, eosinophilia, and elevated immunoglobulins/IgE. METHOD: Comparative case series of 31 patients with IgG4-RD and 13 patients with L-HES. RESULTS: Peripheral blood eosinophilia was present in eight of 31 patients with IgG4-RD compared to 13 of 13 patients with L-HES (median eosinophils 0.4 vs 7.0 giga/L, P=.001) and 12 of 20 patients with IgG4-RD had increased serum IgE compared to eight of 13 patients with L-HES, P=.930. Twenty-seven of 30 patients with IgG4-RD had elevated serum IgG4 compared to five of 12 patients with L-HES (median IgG4 9.6 g/L vs 0.80 g/L, P=.002). Flow cytometry demonstrated an aberrant T-cell phenotype in 7 of 23 patients with IgG4-RD and 13 of 13 patients with L-HES (P<.001). T-cell clonality by PCR was positive in 12 of 23 patients with IgG4-RD vs 10 of 13 patients with L-HES (P=.143). Patients in both groups received corticosteroids as first-line therapy. For refractory disease in IgG4-RD, rituximab was the most common steroid-sparing agent, whereas in L-HES, it was pegylated interferon-α-2a. CONCLUSION: The overlapping features of these two diseases with divergent treatment options demonstrate the importance of familiarity with both entities to optimize diagnosis and treatment.

Post-radiation epithelioid angiosarcoma of the urinary bladder and prostate.

Angiosarcoma of the lower urinary tract is exceedingly rare. A minority of cases are associated with local radiotherapy. Epithelioid angiosarcoma is a variant of angiosarcoma composed of large rounded epithelioid endothelial cells that are positive for cytokeratin on immunostaining. There are only two cases of post-radiation epithelioid angiosarcoma reported in the urinary bladder, and none in the prostate gland. We report a case of epithelioid angiosarcoma involving the urinary bladder and prostate in a patient with a history of radiotherapy for prostatic adenocarcinoma. A brief review of literature regarding post-radiation epithelioid angiosarcomas in the lower urinary tract is discussed.

Impact of time from diagnosis to initiation of curative-intent chemotherapy on clinical outcomes in patients with classical Hodgkin lymphoma.

The impact of treatment delays on outcomes in Hodgkin lymphoma (HL) is currently unknown. Time from definitive histologic diagnosis to first ABVD treatment (TDT) was calculated in 810 adults with HL: 365 (45%) TDT ≤4 weeks, 369 (46%) TDT 5-8 weeks, 76 (9%) TDT >8 weeks. The 5-year overall survival (OS) was 92% TDT ≤4 weeks, 92% TDT 5-8 weeks, and 83% TDT >8 weeks (p = 0.007). The 5-year disease-specific survival (DSS) was 93% TDT ≤4 weeks, 95% TDT 5-8 weeks, and 87% TDT >8 weeks (p = 0.094). The 5-year progression-free survival (PFS) was similar between groups (p = 0.139). In the multivariate analysis, TDT >8 weeks was not associated with worse OS, DSS, or PFS. Despite the univariate association between initiation of ABVD >8 weeks and worse OS, these data do not support such cut-off to improve outcomes. Nevertheless, clinicians should make every effort possible to initiate curative-intent chemotherapy as soon as a diagnosis of HL is established.