Histopathological Subtypes Research Articles

Oncological and functional outcomes of patients who underwent open partial nephrectomy for kidney tumor.

To report long-term functional and oncological outcomes of OPN Methods: We enrolled 182 patients who underwent consecutive OPN with a diagnosis of kidney tumor in our clinic between April 2002 and February 2020 and were selected from our prospective OPN database. Preoperative demographic and clinical characteristics, intraoperative and pathological results, and patients' postoperative functional and oncological follow-up data were retrospectively analyzed. Overall survival (OS) and disease- free survival (DFS) were evaluated using Kaplan-Meier survival analysis. The time-dependent variation between preoperative and postoperative functional results was statistically analyzed and presented in a graph. The mean age was 54.4 ± 10.8 yr, and the median age-adjusted Charlson comorbidity index (ACCI) was 1 (interquartile range [IQR] 0-1). The mean tumor size was 3.1 ± 1.2 cm, and the median RENAL score was 6 (IQR 5-8). The most common malign histopathological subtype was clear cell carcinoma with 76.6%, and five cases (3.4%) had positive surgical margins (PSMs). The most common surgical techniques were the retroperitoneal approach (98.9%) and cold ischemia (88.5%). Estimated glomerular filtration rate (eGFR) preservation was 92% (80.8-99.3, IQR), which translates to 32% chronic kidney disease (CKD) upstaging. Acute kidney injury (AKI) was detected in 27 (14.8%) patients according to RIFLE criteria. The intraoperative complication rate was 5.5%, and the postoperative overall complication rate (Clavien-Dindo 1-5) was 30.2%. Major complications (Clavien-Dindo 3-5) were observed in 13 (7.1%) patients. The median oncological follow-up was 42 mo (21.3- 84.6, IQR), and the 5- and 10-yr OS were 90.1% and 78.6%, 5 and 10-yr DFS were 99.4% and 92.1%, respectively. No local recurrence was observed in 5 (3.4%) patients with PSMs; only one had distant metastasis in the 8th postoperative month. The retrospective design, the small number of patients who underwent PN based on mandatory indication, and one type of surgical approach may limit the generalizability of our findings. This study confirms excellent long-term oncologic and functional outcomes after OPN in a cohort of patients selected from a single institution. In light of the information provided by the literature and our study, our recommendation is to push the limits of PN under every technically feasible condition in the treatment of kidney tumors to protect the kidney reserve and achieve near-perfect oncological results.

The Impact of BRAF V600E Mutation Allele Frequency on the Histopathological Characteristics of Thyroid Cancer.

A BRAF V600E mutation in papillary thyroid cancer (PTC) has been shown to be associated with aggressive behavior. Nevertheless, not all BRAF V600E PTCs behave aggressively. Allele frequency (AF) is the number of mutated molecules divided by the total number of wild-type molecules at a specific location in the genome. The relationship between BRAF V600E AF and the histopathological features of thyroid malignancies is not well understood. We hypothesized that the BRAF V600E AF will correlate directly with aggressive histopathological behavior. The aim of this study was to examine this relationship. A retrospective chart review was performed for patients treated for BRAF V600E thyroid malignancies from 2019 to 2022 at McGill University tertiary care hospitals (n = 317). Patients with BRAF V600E-positive malignancies that included information on AF were included (n = 44). The correlation between AF and tumor histopathological features was analyzed. Out of the 44 nodules with a BRAF V600E mutation, those with aggressive features of PTC had a mean AF of 25.8%, which was significantly higher than the non-aggressive group with a mean AF of 10.25% (p = 0.020). Additionally, there was a statistically significant difference in mean AF between patients with a positive sentinel LN (29%) and those with a negative sentinel LN (17.8%) (p = 0.021). Classical PTC was present in 29.5% (13/44) of nodules, with a mean AF of 15.6%. The tall cell subtype was found in 64% (28/44) of nodules, with a mean AF of 23%. Solid and hobnail subtypes were less common in this study, and there was no statistically significant relationship between AF and histopathological subtypes (p = 0.107). Nodules smaller than 1cm had a mean AF of 13.3%, while nodules ranging from 1 2cm had a mean AF of 20.6%, and those larger than 2cm had a mean AF of 27.7%. However, no statistical difference was observed between AF and nodule size (p = 0.160). In this study, BRAF V600E mutations in conjunction with AF help to determine whether thyroid malignancies will display aggressive behavior. This pre-operative finding can help thyroid specialists to determine the extent of thyroidectomy and whether lymph node dissection is required.

Clinicopathological Profile of Colorectal Adenocarcinoma in the Anatomical Pathology Laboratory of Dr. Soedarso Hospital Pontianak

Background: Colorectal adenocarcinoma is ranked third globally in the category of the most commonly diagnosed cancers, as reported by the Global Burden of Cancer (GLOBOCAN) survey in 2020. This condition ranks as the second leading cause of death from cancer with a mortality of 9.40%. Therefore, this study aimed to discover the clinicopathological profile of colorectal adenocarcinoma in the Anatomical Pathology Laboratory of Dr. Soedarso Hospital Pontianak in 2017–2020. Methods: This descriptive study used secondary data from the histopathology reports of the Anatomical Pathology Laboratory obtained by total sampling, which were processed using Microsoft Excel. Results: The total number of colorectal adenocarcinoma patients was 148, and the majority were in the category of 53–61 years, accounting for 30.41%, and 51.35% were female. The majority of the anatomical sites of tumors were in the “Rectum Not Otherwise Specified (NOS)”, with a percentage of 35.14%. The most frequent histopathological subtype was adenocarcinoma NOS, accounting for 85.81%, while the majority of differentiation grade was well differentiated, with a percentage of 90.54%. The most TNM (Tumor, Node, Metastatic) staging system of the American Joint Committee on Cancer (AJCC) was IIA (33.78%). Based on the classification using the Dukes staging system, the most stage suffered by patients was C2 with a percentage of 39.86%. Conclusions: In conclusion, the incidence of diagnosed colorectal adenocarcinoma cases increased yearly in the Anatomical Pathology Laboratory of Dr. Soedarso Hospital Pontianak. Further study of the clinical characteristics and analysis of risk factors in colorectal adenocarcinoma patients were important to support the development of effective preventive strategies.

Correlation of Histopathologic Subtypes of Primary Aldosteronism with Clinical Phenotypes and Postsurgical Outcomes.

Clinical implications of unilateral primary aldosteronism (PA) histopathology remain to be determined in various ethnic populations. We examined the histopathology of unilateral PA using CYP11B2 immunostaining in relation to clinical phenotypes and postsurgical outcomes. Patients consecutively operated for unilateral PA from 2010 to 2020 at 3 tertiary hospitals in South Korea were retrospectively enrolled. Adrenals with solitary aldosterone-producing adenomas and/or dominant aldosterone-producing nodules were classified as the classical and the others as the nonclassical groups. The classical group was subdivided into mixed or solitary group according to whether other aldosterone-producing lesions coexist or not. Of the 240 cases, 124 were solitary, 86 mixed, and 30 nonclassical. Baseline serum potassium concentration was lower in the solitary group than the mixed or nonclassical group. Plasma aldosterone concentration after saline loading was the highest in the solitary group (median 31.65 ng/dL), followed by the mixed group (median 25.40 ng/dL), and the lowest in the nonclassical group (median 14.20 ng/dL). Solitary and mixed groups showed higher lateralization indices and lower contralateral indices than the nonclassical group. The contralateral index was lower in the solitary group than the mixed group. At 6 to 12 months after adrenalectomy, fewer antihypertensive medications were required for the solitary and mixed groups than the nonclassical group. The solitary group, followed by the mixed group, was associated with more severe hyperaldosteronism and more suppressed aldosterone production from the contralateral side than the nonclassical group. Histopathologic phenotypes were related to the clinical manifestations and may suggest postoperative prognosis.

Comparing extracellular volume fraction with apparent diffusion coefficient for the characterization of breast tumors

PurposeTo investigate the feasibility of dual-energy CT (DECT)-derived extracellular volume (ECV) fraction for characterization of breast tumors, compared to apparent diffusion coefficient (ADC) and validated against histopathological findings. Material and methodsThe ECV fraction and ADC were prospectively assessed in patients with breast tumors using chest DECT and breast MRI. The diagnostic performance of ECV fraction and ADC was accessed in predicting breast histopathological subtypes and pathological complete response (pCR) status. Histopathological sections were analyzed by digital image analysis. Pearson’s correlation analysis was used to correlate between DECT and histopathological ECV fractions. ResultsThis study included 271 patients, with 314 breast lesions (61 benign and 253 malignant). The ECV fraction and ADC showed comparable area under the curve (AUC) for distinguishing benign from malignant lesions (p = 0.123) and invasive carcinoma from ductal carcinoma in situ (p = 0.115). There were significant differences in ECV fraction between different hormone receptors and Ki67 states (p = 0.001 ∼ 0.014), while ADC values only differed among various Ki67 states (p < 0.001). The ECV fraction was lower (p = 0.007), ADC was higher (p = 0.013) in pCR than in non-pCR group, with an AUC of 0.748 and 0.730 (p = 0.887), respectively. There was a positive correlation between DECT and histopathological ECV fractions (r = 0.615, p < 0.01). ConclusionsRoutine chest DECT-derived ECV fraction is a viable quantitative imaging biomarker for predicting histopathological subtypes and pCR in patient with breast tumors, and correlated well with histopathology finding.

The Effect of Histopathological Subtype on 5 Year and 10 Year Overall Survival in Primary Malign Tumors of the Chest Wall

Primary tumors of the chest wall are rare tumors comprising 5% of thoracic neoplasms. The current study was designed to evaluate the effect of histopathological subtype on the 5-year and 10-year overall survival and regional recurrence in primary malignant tumors of the chest wall. From December 2007 to December 2019, the data of 20 patients were analyzed. Overall survival rates, median overall survival, regional tumor recurrence and median disease-free survival rates were compared retrospectively between histopathological subtypes. Chondrosarcoma (n=7), desmoid tumor (n=6), undifferentiated pleomorphic sarcoma [(UPS), (n=4)], Ewing's sarcoma (n=1), malignant peripheral nerve sheath tumor (n=1), and liposarcoma (n=1) were the subtypes identified. A lower median overall survival was detected in the UPS histopathological subtype (p = 0.004). The 5 and 10-year overall survival rates in the chondrosarcoma group were 71% and 37%, respectively; desmoid tumors were found in 83% and 42%, respectively. There was no patient with 5-year survival in UPS. A shorter median overall survival was found in lateral wall masses compared to anterior and posterior wall masses (p = 0.001). During the follow-up, 10 patients (50%) died. It was observed that the median disease-free survival in the UPS subtype was shorter compared to the other subtypes (p = 0.002). The regional recurrence rate was 57%, 17% and 75% in chondrosarcoma, desmoid tumor and UPS, respectively. In UPS, a primary malignant tumor of the chest wall, 5-year and 10-year overall survival rates and median overall survival; it was found to be significantly shorter than the chondrosarcoma and desmoid tumor groups.

Unique clinical and prognostic behavior of patients diagnosed with combined exophytic and inverted papilloma histologic subtype.

To evaluate the clinical and prognostic behaviors of sinonasal papillomas. Patients diagnosed with sinonasal papilloma were reviewed between 2001 and 2016 at a tertiary rhinology practice. Using pathology-specific electronic medical record software, patients diagnosed with sinonasal papilloma were identified. Four subcategories of this lesion were identified: inverting (IP), exophytic (EP) oncocytic (OP) and inverting + exophytic (IP + EP) papillomas. A total of 107 patients were identified with unique sinonasal papilloma diagnoses. Of these, the majority were diagnosed with IP (87, 81.3%). The subpopulation of patients co-diagnosed with IP and EP (IP + EP) was unique with respect to clinical presentation and prognosis relative to both the IP and EP alone populations. IP + EP patients (5, 4.7%) were older with an average age of 75.25 years compared to 45 (EP) and 55.26 (IP), p < .0001. IP + EP patients more often presented with epistaxis (60%) compared to 33.3% (EP) and 4.6% (IP). Finally, all IP + EP patients had at least one recurrence of their disease, compared to 33.3% (EP) and 28.5% (IP). Each histopathologic subtype of sinonasal papilloma has unique clinical characteristics and recurrence rates after surgical resection. The subpopulation of patients diagnosed with IP + EP tends to be older, more likely to present with epistaxis, and more likely to recur. Additional investigation and analysis of this subpopulation is warranted. 4.

Characterizing EBV-associated Gastric Carcinoma (EBVaGC): A deep dive into LMP1 expression patterns.

Gastric cancer (GC) is a serious public health issue due to its frequency and severity. It is, for both sexes, one of the most common causes of cancer-related death and is a major contributor to the global burden of disease. Recent data show that Epstein-Barr virus (EBV) has been detected in different histopathological subtypes of gastric carcinoma and that EBV-associated gastric carcinoma (EBVaGC) represents about 10% of all cases. Moreover, the LMP1 protein characterizing the malignant transformation of cells in several cancer models seems to be very rarely expressed in this type of cancer. This study aimed to characterize EBVaGC in our population by detecting LMP1 in gastric carcinomas in about 30 selected patients. The results showed that in our population, nuclear staining predominates, showing that the antrum remains the most sampled site both for these pathologies and for LMP1 positivity (nuclear staining). In general, the LMP1 marking was negative for 22.58%, positive with a nuclear predominance at 64.52%, nuclear and cytoplasmic at 12.90%, and no positive marking for the cytoplasm. Results were not like the different studies on the expression of this oncogenic protein without EBVsCG, probably finding an explanation in the fact that our country is among the endemic regions for this herpes virus. In conclusion, the rate of LMP1 expression among gastric carcinomas does not seem similar to that observed in other countries. This study characterizing EBVaGC in Tizi-Ouzou, Algeria, reinforces the need for further studies to clarify the role of EBV (LMP1) and to explore its potential value as a predictive biomarker for the development of this type of cancer pathology.

Variability in Surveillance Strategies Following Resection of Sacrococcygeal Teratoma

IntroductionSurveillance following sacrococcygeal teratoma (SCT) resection varies. The purpose of this study was to describe the clinical characteristics and outcomes of patients undergoing SCT resection and examine current institutional practices to detect recurrence. MethodsA single-institution retrospective review of children who underwent resection of an SCT from January 1, 2010 to December 31, 2020 was performed. Data were summarized and surveillance strategies compared between histopathologic subtypes using nonparametric methods. ResultsThirty six patients (75.0% female) underwent SCT removal at a median age of 8 d. Histopathology revealed 27 mature teratomas (75.0%), eight immature teratomas (22.2%), and one malignant germ cell tumor (2.8%). Median postoperative follow-up was 3.17 y (interquartile range [IQR]: 2.31-4.38 y). Patients had a median of 2.32 clinic visits per year (IQR: 2.00-2.70), alpha-fetoprotein levels were obtained at a median of 2.01 times per year (IQR: 0-1.66), and surveillance imaging was performed at a median of 2.31 times per year (IQR: 0-2.84). Patients with immature teratomas had alpha-fetoprotein laboratories obtained more frequently than patients with mature teratomas (3.10 times/year versus 0.93 times/year, P = 0.001). There was no significant difference in the number of imaging studies obtained between groups. Two patients (5.6%) developed recurrence, which were identified on magnetic resonance imaging at 191 and 104 d postresection, respectively. ConclusionsPostoperative surveillance practices varied widely. Recurrence was noted in a single malignant case in the first year following resection. Multi-institutional studies are needed to determine the optimal surveillance strategy to detect recurrence of SCT.

Preoperative evaluation of high-risk basal cell carcinoma with line-field confocal optical coherence tomography (LC-OCT) reduces Mohs micrographic surgery stage number: A case-control study

BackgroundMohs micrographic surgery (MMS) is the preferred surgical approach for high-risk basal cell carcinoma (BCC). Pre-surgical tumor margins delineation with line field confocal optical coherence tomography (LC-OCT) is expected to reduce MMS stages number. Objectiveto investigate the effectiveness of LC-OCT preoperative evaluation of high-risk BCC margins in reducing the number of MMS stages to achieve tumor clearance. Patients and methodshigh-risk BCC patients undergoing MMS at Policlinico A. Gemelli Foundation, IRCCS – Rome during January 2018 – December 2022. The LC-OCT group included patients undergoing preoperative lateral tumor margin demarcation by clinical, dermoscopic, and LC-OCT examination; patients in the control group underwent preoperative lateral tumor margin demarcation by clinical and dermoscopic examination only. LC-OCT imaging was compared to MMS histopathological sections. Results63 facial high-risk BCCs from 60 patients, mean age of 68.3 years (SD 11.9). The LC-OCT and the control group included 22 and 41 BCCs, respectively. LC-OCT imaging showed almost perfect agreement with histopathology for low- versus high-risk of recurrence BCC histopathological subtypes discrimination (Cohen’s kappa 0.88). We reported a significant difference in the mean number of MMS stages between the LC-OCT and the control group (1.23 ± 0.43 SD, and 1.89 ± 1.05 SD, respectively; p-value =0.007). At univariate regression analysis, LC-OCT preoperative mapping of BCC tumor margins significantly reduced patients’ risk of undergoing >1 MMS stage (crude odds ratio [ORc]: 0.3 95% CI 0.1–0.8, p-value =0.032). ConclusionLC-OCT preoperative evaluation of high-risk BCC margins significantly reduced the number of MMS stages to achieve tumor clearance.

Lactate dehydrogenase isoform expressions differing impacts on gastrointestinal carcinogenesis

In cancer cells, metabolic alterations support tumor growth, survival, and progression. This study aims to examine the effects of lactate metabolism on the carcinogenesis of gastrointestinal subtypes. Hence, signatures relevant to lactate metabolism were gathered from the molecular signatures database and investigated in the genome-wide expression profiles of gastrointestinal cancer cohorts' using gene sets-based pathway activation scoring analysis. The results of this study represent that the lactate metabolism signatures are significantly expressed across gastrointestinal subtype tumors such as intestinal histopathological subtype of gastric tumor, intraductal papillary mucinous neoplasm (IPMN) subtype of pancreatic cancer, and hepatocellular carcinoma (HCC) stage of liver tumors, respectively. As a result, these metabolisms were dysregulated across subtypes of gastrointestinal carcinogenesis. The identified dysregulation was further reconfirmed by examining corresponding metabolic gene expression patterns across various subtypes encompassing single-cell RNA sequence profiles. These outcomes also reassured that lactate dehydrogenase isoform genes such as LDHA, LDHC, and its transporter gene SLC16A1 are highly enriched in intestinal, IPMN, and HCC subtypes' tumors, respectively. In contrast, LDHB and LDHD genes are vastly elevated in non-tumorous tissues than in gastrointestinal cancer. Furthermore, overall survival plots also reconfirmed that these gene expressions were associated with poor survival in the corresponding subtype's patient cohorts. All of these findings demonstrate the existence of lactate metabolic rewiring and involvement in gastrointestinal carcinogenesis. These results may help develop therapeutic target therapies for malignancies of the gastrointestinal subtype.

Unveiling The Neuropathology Tumour Landscape: 10-Year Statistical Analysis With Global Comparison - Single Centre Experience.

Introduction: Central nervous system (CNS) tumours represent a significant public health issue worldwide, and their incidence and distribution vary across different populations. Although studies on CNS tumours have been conducted in various countries, there is a lack of information regarding their patterns in Macedonia. Therefore, this study is aimed at investigating the distribution, histopathological types and subtypes and demographic features of CNS tumours in our country. Materials and Methods: A cross sectional study was conducted using the electronic database of the Institute of Pathology - Medical Faculty, University "Ss. Cyril and Methodius" in Skopje which contains data from 3286 received and analysed surgical specimens, mainly from the University Clinic of Neurosurgery in Skopje, and a smaller number of surgical specimens from the University Surgical Centre "St. Naum Ohridski" in Skopje between 2012 and 2022. The collected and analysed data includes patient age, sex and histopathological types and subtypes of the tumours. Results: The majority of CNS tumours were diagnosed in adults aged between 50-70, with a male to female ratio of 1.5:1. The most common location of the tumours was the cerebrum, followed by the pituitary gland and cerebellum. The most frequent histological groups were gliomas, with glioblastoma as the most common diagnosis, followed by meningiomas. Conclusion: Following a detailed and thorough review of the CNS tumours in our study, we can conclude that the R. of Macedonia follows global statistics and trends regarding brain tumours.

Clinicopathological assessment of renal tumors in pediatric age group in a sample of Iraqi patients

Background: According to the Iraqi Cancer Registry, renal carcinoma is the 13th most common carcinoma, with 798 registered cases in 2020 and 418 deaths. Methods: This is a cross sectional retrospective study that includes the analysis of 116 randomly selected sample of pediatric patients (74 nephrectomies and 42 biopsies) sent to the Teaching Laboratories of AL-Emamain AL-Kadhmain city (AS), Baghdad medical city, and private laboratories from January 2019 to January 2023. Results: Histopathological diagnosis revealed a ratio from malignant to benign of 7.4:1. Wilm’s tumor was the most common malignant tumor (65.5%), while multicystic renal dysplasia was the most common benign tumor (7.8%). Abdominal pain was the most common clinical feature (67.2%), followed by abdominal mass (20.7%). Regarding malignant cases, Pathological stage I was the most common (39.0%). As for the histopathological subtype, triphasic type was the most common (57.1%), followed by the biphasic type (10.5%). Conclusions, Malignant tumors make up the vast majority of renal tumors. Wilm tumor is the predominant malignant tumor. Fortunately, most cases of Wilm tumors exhibited an early stage and favorable histology. Neuroblastoma was the second most common malignant tumor. The abdominal lump is the most common presentation of pediatric renal tumor.

Quantitative Diffusion-Weighted MR Imaging: Is There a Prognostic Role in Noninvasively Predicting the Histopathologic Type of Uveal Melanomas?

Histopathologically, uveal melanomas (UMs) can be classified as spindle cell, mixed cell and epithelioid cell type, with the latter having a more severe prognosis. The aim of our study was to assess the correlation between the apparent diffusion coefficient (ADC) and the histologic type of UMs in order to verify the role of diffusion-weighted magnetic resonance imaging (DWI) as a noninvasive prognostic marker. A total of 26 patients with UMs who had undergone MRI and subsequent primary enucleation were retrospectively selected. The ADC of the tumor was compared with the histologic type. The data were compared using both one-way analysis of variance (ANOVA) (assessing the three histologic types separately) and the independent t-test (dichotomizing histologic subtypes as epithelioid versus non-epithelioid). Histologic type was present as follows: the epithelioid cell was n = 4, and the spindle cell was n = 11, the mixed cell type was n = 11. The mean ADC was 1.06 ± 0.24 × 10−3 mm2/s in the epithelioid cells, 0.98 ± 0.19 × 10−3 mm2/s in the spindle cells and 0.96 ± 0.26 × 10−3 mm2/s in the mixed cell type. No significant difference in the mean ADC value of the histopathologic subtypes was found, either when assessing the three histologic types separately (p = 0.76) or after dichotomizing the histologic subtypes as epithelioid and non-epithelioid (p = 0.82). DWI-ADC is not accurate enough to distinguish histologic types of UMs.

Clinical Characteristics and Treatment Outcomes of Idiopathic Multicentric Castleman Disease: Data from a Pediatric Cohort

Background: Idiopathic multicentric Castleman disease (iMCD) is a rare, atypical hematologic disorder characterized by diffuse lymphadenopathy and systemic inflammation causing potentially fatal multi-organ system dysfunction. Though the etiology remains unknown, interleukin-6 (IL-6) has been implicated in disease pathogenesis and siltuximab, a monoclonal antibody that antagonizes IL-6, is the only FDA-approved iMCD treatment. Despite substantial morbidity for children with iMCD, the pediatric experience has not been well characterized. It is unclear whether insights gleaned from adults apply to children or whether siltuximab, which was never prospectively studied in a pediatric population, achieves similar response rates in children. We sought to correct this knowledge gap and better characterize pediatric iMCD. Methods: The ACCELERATE longitudinal Castleman disease (CD) natural history registry was interrogated for patients under 18 years of age at time of diagnosis. For each patient, complete medical history and lymph node biopsy slides were collected and extracted, and a panel of clinicians and pathologists performed independent adjudication of the diagnosis. Demographics - including age at diagnosis, histopathologic subtype, clinical subtype, clinical symptoms, and most severe laboratory parameters present within ± 90 days from date of pathological diagnosis were aggregated. Lastly, treatments administered to the cohort of pediatric patients were inventoried and both clinical response (defined as at least 50% reduction in abnormal clinical and laboratory criteria) and durable response (defined as a positive clinical response lasting ≥ 365 days with no other CD treating drug administered in between) were determined. Results: Nineteen pediatric patients were confirmed to have iMCD, of which 14 (74%) were male and 5 (26%) were female (Table 1A). The mean (standard deviation [SD]) age at diagnosis was 13.6 (4.3), with the youngest patient diagnosed at 2 years of age. Much of the cohort demonstrated hypervascular lymph node histology (89.5%). Clinically, 84% of the patients demonstrated the severe TAFRO (thrombocytopenia, anasarca, fever, renal dysfunction/reticulin fibrosis, organomegaly) subtype while 16% were not otherwise specified. 95% of patients presented with constitutional symptoms and all but one patient presented with fatigue and fevers. All 19 patients presented with organomegaly and fluid retention (anasarca, ascites, pleural effusions, and/or peripheral edema). No patients demonstrated CD-specific skin abnormalities (violaceous lymphocytic papules or cherry hemangiomata) or interstitial lymphocytic pneumonitis. Labs indicated significant systemic inflammation, with mean (SD) C-reactive protein, erythrocyte sedimentation rates, and albumin values of 128.3 (102.7) mg/L, 74.5 (42.5) mm/hr, and 2.7 (0.6) g/dL, respectively. Eighteen (95%) patients presented with anemia, with a mean (SD) hemoglobin value of 9.5 (2.2) g/dL. Sixteen (84%) patients demonstrated platelet abnormalities, with 13 patients presenting with thrombocytopenia and three with thrombocytosis. No patient demonstrated hypergammaglobulinemia. Nine patients received three unique siltuximab regimens: siltuximab ± CS (corticosteroids), siltuximab + sirolimus ± CS, and siltuximab + other (other being defined as all other treatments such as rituximab, eculizumab, and ravulizumab) (Table 1B). Siltuximab ± CS was administered to six patients; 83% (n=5) had a positive response, and 60% of responders achieved a durable response. Lastly, two patients with TAFRO died from their disease. Conclusions: Overall, real-world medical record data from a cohort of pediatric iMCD patients enrolled in ACCELERATE reveals high disease burden within this population. A notable degree of TAFRO, the most severe iMCD subtype, was observed within this pediatric cohort, with clinical manifestations and laboratory abnormalities commonly observed in adult iMCD. This makes this population particularly vulnerable and highlights the need for prompt and accurate treatment. We also observed a high response rate to siltuximab ± CS in this small cohort, supporting its use in pediatric iMCD. Further research examining the effectiveness of siltuximab in a larger cohort of pediatric patients as well as other treatments is needed to identify optimal treatment approaches.

Patterns of Care and Outcome in Adolescent and Young Adults (AYA) Lymphomas- a Multicenter HCC (Hematologic Cancer Consortium) Registry Study from India

Introduction There are no recommendations pertaining to lymphoma in AYA population. It represents a paramount opportunity for fostering collaborative research among pediatric and medical oncologists. Prior to embarking on any collaborative interventional research, comprehensive demographic data, patterns of care, and outcomes related to AYA lymphomas are imperative. Hence, the HCC registry database can be utilized to do this analysis of all AYA lymphoma in India which will set the benchmark for future research in this area. Methods This was a retrospective study including data from participating member centers of the HCC registry. Data was collected using an online data capture program, which is already in place as part of the HCC registry and has been in use for the past 5 years. Each center maintains its source documents and is responsible for data accuracy. All patients diagnosed with lymphoma between January 01, 2020, and June 31, 2022, were included in the study. The treatment patterns for AYA lymphomas vary from intensive protocols like in the pediatric age group to less intense protocols used in adults. This registry data captured this heterogeneity in treatment patterns and outcomes. The primary endpoint of the study was event-free survival (EFS) which was defined as the time from the first cycle of chemotherapy to progression, relapse, second malignancy, or death. The secondary outcomes were response rates and overall survival. Results The data was collected from eight participating centers of India out of which five are public sector hospitals and three are trust-based private hospitals. A total of 677 AYA lymphomas were registered between January 01, 2020, and June 31, 2022. Treatment was given to 582 patients and the follow-up data was available for 570 patients. The median age of the cohort was 23 years (IQR-19, 27) with 65% of them being males. Almost 50 % of patients had Hodgkin lymphoma and the rest were non-Hodgkin lymphoma (NHL) as depicted in Figure 1. Among NHLs; DLBCL, T-LBL, PMBCL, ALCL, and Burkitt lymphoma were seen in 113(17%), 39(6%), 36(5%),28(4%), and 19(3%) respectively. PETCT was done in 70% patients at baseline. Early-stage disease was seen in 233 patients (35%), advanced stage in 366 patients (56%), and 60 patients (9%) were not staged at baseline. Bulky mediastinum was seen in 1/4 th of the patients out of which the majority (85%) were Hodgkin lymphoma and PMBCL. Extra nodal site involvement was seen in 43% of patients out of which marrow involvement constituted almost half. Out of 677 patients, 582 patients (86%) received treatment at their respective centers and only 5 % of patients could not receive any treatment due to financial constraints. Among 298 treated cases of Hodgkin lymphoma, 245(82 %) patients received ABVD while escBEACOPP was given to 28(9%) patients. In DLBCL, out of 87 patients, 59(68%) received CHOP-R, 10(11%) received DA-REPOCH, 8(9%) received GMALL NHL protocol and the rest 10(11%) received other intensive regimens. Around one-third(36%) patients received radiation therapy out of which 90 patients (57%) received it as part of definitive treatment and 50 (31%) patients received it as consolidation to residual site. The median follow-up of the entire cohort was 13 months(IQR-8, 12). Out of 570 patients where follow-up was available, the overall EFS was 76. % ± 2.4%. The EFS outcome according to the histopathological subtype is depicted in Figure 2. Relapse or progression occurred in 72 patients (12.5%) out of which 50(72%) could receive any form of salvage therapy including transplant. The most common cause of death was progressive disease in 18 patients (50%) and death due to toxicity in 3(8%), and unknown causes in 16(40%) patients. The presence of bulky disease or bulky mediastinum did not have an impact on EFS outcome.There was no difference in EFS between DLBCL or High-grade B- NHL NOS. Conclusion This is the one of largest real-world data on AYA lymphoma. The majority were Hodgkin lymphoma followed by DLBCL. Most patients received adult-type regimens or Hodgkin as well as non-Hodgkin lymphoma. The use of radiation was high (1/3 rd) which could be due to a higher burden of bulky and mediastinal disease in our cohort. The EFS outcomes are comparable to the published literature. This data will set the benchmark for future collaborative studies in India and abroad for AYA lymphoma.

Genetic Subtyping Using Whole Exome Sequencing across Large B Cell Lymphoma Entities in a Series of 109 DLBCL and Plasmablastic Lymphoma Cases

Background: Diffuse Large B Cell Lymphomas are still a significantly heterogeneous disease with few molecularly defined entities. Recently genomic based algorithms have been proposed for DBCL NOS disease classification, including the Lymphgen tool 1. Other large B cell lymphoma entities, including High Grade BCL Dual Hit or plasmablastic lymphoma remain poorly characterized according to this molecular based clustering methods. Here we sought to apply this tool for disease classification in a series of 109 large B cell lymphoma cases derived from GELTAMO clinical trials (NCT01848132 and NCT2015-005390-21) and retrospective multicentric series to confirm its application across different large B cell lymphoma entities. Methods: We retrieved FFPE and liquid biopsy diagnostic samples from 109 cases and performed histopathological confirmation, FISH testing and whole exome sequencing (Agilent Sureselect v6) by NGS. Sequencing data and available fusion data for BCL2 and BCL6 were used to classify the cases according to Lymphgen (https://llmpp.nih.gov/lymphgen). Results: 109 cases were classified as different large B cell lymphoma entities, including 31 DLBCL NOS GCB type, 8 HGBCL/DLBCL DH/NOS, 41 DLBCL NOS non-GCB type, 22 plasmablastic lymphoma, 3 THRLBCL, 1 PMBL, 2 DLBCL NOS and 1 3B Follicular Lymphoma. After WES median Tumor Mutation Burden was 972. Overall genetic classification by Lymphgen was obtained in 53 cases (49%) with the remaining 56 cases considered unclassified (molecular subtype other/NOS). Of the genetically identified cases, 18 were classified as ST2 (33%), 15 were considered EZB (28%), 5 BN2 (10%) and 3 MCD (5%). Interestingly 12 (22%, overall, 11%) were genetically composite, including 8, ST2/EZB; 1, ST2/BN2; 1, ST2/MCD and 2 ST2/EZB/MCD. According to histopathological subtype 17 GCB type DLBCL were classified as EZB (8, 47%), ST2 (5, 30%) and BN2 (1, 6%). 3 cases (17%) were genetically composite. 6 out of 8 cases of HGBCL/DLBCL DH/NOS were classified as either EZB (2), ST2 (2) or composite EZB/ST2 (2). 19 non-GCB type DLBCL were classified as ST2 (5, 26%), BN2 (4, 21 %), EZB (3, 16 %) and MCD (3, 16%). 4 cases were genetically composite (21%). Interestingly, plasmablastic lymphomas showed ST2 genetic features, found in 5 out of 22 (23%) and composite ST2/EZB in 2 cases. Genes overrepresented in the ST2 cluster include TET2, PRRC2C, STAT3,DOCK8 and CLTC. Plasmablastic Lymphomas classified as other showed recurrent mutations in PRRC2C, PABPC1, TRRAP, PRKCB, EP300 and TP53. Conclusions: ST2 and EZB genetic groups stand as the most frequent genetic subtypes of DLBCL NOS. While ST2 is found in either GCB and non-GCB subtypes, EZB is found preferentially in cases with the GCB phenotype, including GCB type DLBCL and HGBCL/DLBCL DH. In comparison with already published series we found a relatively higher prevalence of the ST2 genetic subtype among DLBCL NOS. MCD and BN2 genetic subtypes are restricted to the non-GCB subtype, but its prevalence is relatively low. Importantly, a significant fraction of cases (~50%) is still genetically unclassified (molecular subtype NOS) using WES and FISH-derived fusion data. Proper identification of the A53 cluster and relevant dysregulated pathways in the molecular NOS group require more research. Specific large B cell lymphoma entities such as plasmablastic lymphoma show features of ST2 genetic subtype in a significant fraction of tumors. These features include JAK/STAT3 pathway activation related genes and fit well with already published data 2,3. In addition, recurrent mutations in TET2, involved in epigenetic regulation of gene expression and TRRAP, target of C-MYC transcriptional activation, were enriched in this molecular subtype of plasmablastic lymphoma. Importantly ~70% remained unclassified. Mutations in this group are recurrently found in PRRC2C as well as PABPC1, both involved in VEGFA-VEGFR2 signaling. In summary, DLBCL NOS molecular subtyping supplies exact molecular classification in ~50% of our cohort. ST2 and EZB subtypes constitute ~60% of the cases with a fraction of ~15% of composite ST2/EZB. Application of the molecular classifier to plasmablastic lymphomas shows intraspecific genetic diversity and points toward dysregulation of JAK/STAT, MAPK/Erk and VEGFA-VEGFR2 signaling as well as MYC transcriptional activation. REFERENCES 1. PMID: 32289277 2. PMID: 33225311 3. PMID: 32273478

PSMA-Expression Is Highly Associated with Histological Subtypes of Renal Cell Carcinoma: Potential Implications for Theranostic Approaches.

In renal cell carcinoma (RCC), accurate imaging methods are required for treatment planning and response assessment to therapy. In addition, there is an urgent need for new therapeutic options, especially in metastatic RCC. One way to combine diagnostics and therapy in a so-called theranostic approach is the use of radioligands directed against surface antigens. For instance, radioligands against prostate-specific membrane antigen (PSMA) have already been successfully used for diagnosis and radionuclide therapy of metastatic prostate cancer. Recent studies have demonstrated that PSMA is expressed not only in prostate cancer but also in the neovasculature of several solid tumors, which has raised hopes to use PSMA-guided theranostic approaches in other tumor entities, too. However, data on PSMA expression in different histopathological subtypes of RCC are sparse. Because a better understanding of PSMA expression in RCC is critical to assess which patients would benefit most from theranostic approaches using PSMA-targeted ligands, we investigated the expression pattern of PSMA in different subtypes of RCC on protein level. Immunohistochemical staining for PSMA was performed on formalin-fixed, paraffin-embedded archival material of major different histological subtypes of RCC (clear cell RCC (ccRCC)), papillary RCC (pRCC) and chromophobe RCC (cpRCC). The extent and intensity of PSMA staining were scored semi-quantitatively and correlated with the histological RCC subtypes. Group comparisons were calculated with the Kruskal-Wallis test. In all cases, immunoreactivity was detected only in the tumor-associated vessels and not in tumor cells. Staining intensity was the strongest in ccRCC, followed by cpRCC and pRCC. ccRCC showed the most diffuse staining pattern, followed by cpRCC and pRCC. Our results provide a rationale for PSMA-targeted theranostic approaches in ccRCC and cpRCC.

NIMG-89. CNS-ISOLATED RICHTER’S TRANSFORMATION: THE FALLIBILITY OF NEURO-IMAGING AND THE CRITICAL ROLE OF BRAIN BIOPSY IN A CHALLENGING DIAGNOSIS

Abstract INTRODUCTION An 81-year-old male was admitted for acute encephalopathy and failure to thrive. Workup revealed a lymphocyte-predominant leukocytosis, prominent axillary and mediastinal lymphadenopathy on CT, and multiple supra-tentorial FLAIR-hyperintense lesions that were homogenously contrast-enhancing. Axillary lymph node biopsy demonstrated small lymphocytic lymphoma (SLL), a variant of CLL. Despite concern for CNS malignancy, brain biopsy was initially deferred since the patient’s brain lesions were attributed to SLL metastasis. However on hospital day 15, he developed partial seizures, prompting stereotactic biopsy which revealed DLBCL. DATA/DISCUSSION Our case highlights the pitfalls of relying solely upon neuro-imaging to diagnose Richter’s transformation (RT) isolated to the CNS. First, MRI does not differentiate CNS metastasis of systemic lymphoma from CNS RT. A review of 35 biopsy or LP-proven cases of CNS-isolated RT showed imaging characteristics consistent with primary and metastatic CNS lymphoma. When parenchymal lesions are present, all are T2/FLAIR hyper-intense; 60% are unifocal (40% multifocal); and 95% homogenously enhance. Second, CNS-isolated RT is at least 3 times rarer than CNS metastases of CLL. Among patients with CLL, ~1% will eventually exhibit CNS metastasis but &amp;lt; 0.3% will develop CNS-isolated RT. In patients with known CLL and no evidence of high-grade transformation, it is reasonable to attribute brain lesions to CNS metastasis of CLL as opposed to RT, absent a definitive tissue diagnosis. CONCLUSION These data emphasize the importance of biopsy in the workup of CNS lymphoma, especially since treatment differs based on histopathological subtype. Given its chronic indolent course, SLL is typically managed expectantly, whereas the aggressive nature of DLBCL warrants more intensive chemotherapy. Our case also shows that in patients with suspicious CNS lesions, presence of systemic malignancy does not eliminate the need for brain biopsy, and that clinical deterioration should prompt biopsy if not already performed.

Deep histopathology genotype–phenotype analysis of focal cortical dysplasia type II differentiates between the GATOR1-altered autophagocytic subtype IIa and MTOR-altered migration deficient subtype IIb

Focal cortical dysplasia type II (FCDII) is the most common cause of drug-resistant focal epilepsy in children. Herein, we performed a deep histopathology-based genotype–phenotype analysis to further elucidate the clinico-pathological and genetic presentation of FCDIIa compared to FCDIIb. Seventeen individuals with histopathologically confirmed diagnosis of FCD ILAE Type II and a pathogenic variant detected in brain derived DNA whole-exome sequencing or mTOR gene panel sequencing were included in this study. Clinical data were directly available from each contributing centre. Histopathological analyses were performed from formalin-fixed, paraffin-embedded tissue samples using haematoxylin–eosin and immunohistochemistry for NF-SMI32, NeuN, pS6, p62, and vimentin. Ten individuals carried loss-of-function variants in the GATOR1 complex encoding genes DEPDC5 (n = 7) and NPRL3 (n = 3), or gain-of-function variants in MTOR (n = 7). Whereas individuals with GATOR1 variants only presented with FCDIIa, i.e., lack of balloon cells, individuals with MTOR variants presented with both histopathology subtypes, FCDIIa and FCDIIb. Interestingly, 50% of GATOR1-positive cases showed a unique and predominantly vacuolizing phenotype with p62 immunofluorescent aggregates in autophagosomes. All cases with GATOR1 alterations had neurosurgery in the frontal lobe and the majority was confined to the cortical ribbon not affecting the white matter. This pattern was reflected by subtle or negative MRI findings in seven individuals with GATOR1 variants. Nonetheless, all individuals were seizure-free after surgery except four individuals carrying a DEPDC5 variant. We describe a yet underrecognized genotype–phenotype correlation of GATOR1 variants with FCDIIa in the frontal lobe. These lesions were histopathologically characterized by abnormally vacuolizing cells suggestive of an autophagy-altered phenotype. In contrast, individuals with FCDIIb and brain somatic MTOR variants showed larger lesions on MRI including the white matter, suggesting compromised neural cell migration.