Multifocal Tumors Research Articles

INCIDENTALLY VS. NON-INCIDENTALLY DIAGNOSED PAPILLARY THYROID CARCINOMA: ARE THERE DIFFERENCES?

Compare incidental vs. non-incidental TC (ITC vs. NITC) regarding demographic, clinical, histological data and 5-year clinical outcomes. Retrospective analysis of 225 papillary TC (PTC) cases that completed a 5-year follow-up. Created 2 groups: ITC (including the incidentalomas) and NITC (cases of palpable or visible nodules or with thyroid compressive complaints). Included 225 PTC (122 were ITC). There were 95 women in ITC and 78 in NITC. ITC patients were significantly older (53.3±14.8 vs 47.2±17.7, p=0.006). Groups had no differences in family history of TC. ITC mean tumour size was smaller (19.1±9.2 vs 28.6±16.2, p<0.01). Tumours >20mm comprised 36.1% of ITC and 58.2% of NITC. We found no differences in tumour multifocality, histological thyroiditis, aggressive PTC subtypes, capsule or lymph-vascular invasion and gross extrathyroidal extension. There were no differences regarding the number of patients submitted to RAI or in RAI activity. pTMN staging showed higher prevalence of T3a and T4 cases (p<0.01), and M1 status (p=0.025) in NITC. There were no differences in the rates of persistence of disease. Logistic regression showed that the diagnostic modality had no impact on the 5-year clinical outcome. ITC patients were older and had smaller tumours. NITC showed no worst histological features or 5-year clinical outcome. Approximately, one third of ITC had diameters >20mm. As even large tumours can be ITC, overdiagnosis can be the most likely cause for the TC increasing incidence.

Demonstration of Epstein-Barr Virus by In Situ Hybridization in Papillary Thyroid Carcinomas Developing on Background of Hashimoto's Thyroiditis.

This study aimed to demonstrate the role of Epstein-Barr Virus (EBV) in papillary thyroid carcinomas (PTC) developing on the background of Hashimoto's thyroiditis (HT). The presence of EBV in tumoral tissue, lymphocytes, and peritumoral normal thyroid tissue was investigated using the in situ hybridization method in paraffin blocks. The subtypes of PTC, tumor diameter, TNM stage, multifocality, invasion of thyroid capsule, perineural invasion, and muscular tissue invasion were identified and compared according to EBV involvement. Eighty-one patients with HT diagnosis, with 93.8% (n=76) female and 6.2% (n=5) male, were included in the study. Papillary microcarcinoma was the pathological diagnosis in 24.2% (n=15) of the cases. EBV was identified in 58.06% (n=36) of the tumor cells nuclei, 58.06% (n=36) in the tumor cell cytoplasm, 16.12% (n=10) in tumor infiltrative lymphocytes, and 53.2% (n=33) in normal parenchymal follicle epithelial cells (NPFEC). In the T2 stage, the rate of EBV nuclear positivity in patients was significantly higher (p=0.034). The classic variant of papillary carcinoma was accompanied by a significantly higher rate of EBV-negative NPFEC (67.6%, p=0.049). In multifocal tumors, EBV positivity was found to be significantly higher in lymphocytes in the surrounding tissues (58.3%, p=0.034). A significant increase in EBV positivity in the surrounding tissue lymphocytes was observed in multifocal PTC developing on a background of HT. This suggests a possible association between HT and EBV.

Traversing the Terrain: Potential Pitfalls within the AJCC 8th Edition Staging System for Lip and Oral Cavity Cancers.

In 1977, the American Joint Committee on Cancer (AJCC) introduced the inaugural Cancer Staging Manual, which implemented the T (tumor extent), N (regional lymph node status), and M (presence or absence of distant metastasis) staging system. This systematic approach aimed to convey the extent of disease across various cancer types, providing clinicians with a practical framework to plan treatment strategies, predict prognosis, and assess outcomes. The AJCC 8th edition, effective from January 1, 2018, continues this tradition. However, certain shortcomings persist in the AJCC 8th edition, as identified through clinical experience. Specifically, challenges arise in accurately assessing depth of invasion in unique histological variants of oral squamous cell carcinoma (e.g., Oral verrucous carcinoma, Carcinoma cuniculatum, and Papillary squamous cell carcinoma) and minor salivary gland tumors. Additionally, discrepancies exist in the perception of bone invasion patterns and in reporting practices. There is also a need for staging guidelines for malignant odontogenic tumors and multifocal tumors of the oral cavity, supplemented by diagrammatic representations. Lastly, there is a call for comprehensive staging criteria for carcinomas of the ear, external auditory canal, and temporal bone. We advocate for the inclusion of these considerations in future editions of the AJCC Cancer Staging Manual.

Rare presentation of recurrent ovarian carcinoma with secondary Budd–Chiari syndrome: a case report

BackgroundBudd–Chiari syndrome (BCS) is a rare condition, usually associated with hematological disorders such as thrombotic diathesis and hypercoagulability. Serum CA-125 level is an established tumor marker of ovarian malignancy; however, cases of primary BCS may also show raised CA-125 levels. BCS in a case of ovarian carcinoma is usually primary in nature due to hypercoagulable state, and raised CA-125 levels with tender hepatomegaly in a treated case of ovarian carcinoma usually imply metastatic recurrence in the liver. However, our case demonstrates an atypical secondary cause of BCS in such a patient caused by extrinsic compression of IVC due to recurrent disease.Case presentationWe report an unusual case of a 69-year-old female who presented with nausea and abdominal pain. She had a 7-year-old history of endometrioid carcinoma of the right ovary for which she underwent total abdominal hysterectomy, bilateral salpingo-oophorectomy, omentectomy and pelvic lymph node dissection along with adjuvant chemotherapy. Currently, she had right hypochondrium tenderness, deranged liver function tests (LFT) and raised CA-125 levels, which raised suspicion of hepatic metastasis. However, CECT abdomen revealed peripheral mottled enhancement of liver with multifocal extrahepatic tumor deposits, one of them causing compression of inferior vena cava (IVC) implying a diagnosis of secondary Budd–Chiari syndrome.ConclusionsIn a background of treated ovarian malignancy with raised CA-125 levels and deranged LFT, primary suspicion is of hepatic tumor recurrence. However, in our case, radiological investigation revealed diagnosis of secondary Budd–Chiari syndrome due to perihepatic metastatic recurrence with the absence of frank intrahepatic lesions.

Genomic characteristics and evolution of Multicentric Esophageal and gastric Cardiac Cancer

BackgroundEsophageal carcinoma (EC) and gastric cardiac adenocarcinoma (GCA) have high incidence rates in the Chaoshan region of South China. Multifocal esophageal and cardiac cancer (MECC) is commonly observed in this region in clinical practice. However, the genomic characteristics of MECC remains unclear.Materials and methodsIn this study, a total of 2123 clinical samples of EC and GCA were analyzed to determine the frequency of multifocal tumors, as well as their occurrence sites and pathological types. Cox proportional hazards regression was used to model the relationship between age, sex, and tumor state concerning survival in our analysis of the cohort of 541 patients with available follow-up data. We performed whole-genome sequencing on 20 tumor foci and 10 normal samples from 10 MECC patients to infer clonal structure on 6 MECC patients to explore genome characteristics.ResultThe MECC rate of EC and GCA was 5.65% (121 of 2123). Age and sex were potential factors that may influence the risk of MECC (p < 0.001). Furthermore, MECC patients showed worse survival compared with single tumor patients. We found that 12 foci from 6 patients were multicentric origin model (MC), which exhibited significant heterogeneity of variations in paired foci and had an increased number of germline mutations in immune genes compared to metastatic model. In MC cases, different lesions in the same patient were driven by distinct mutation and copy number variation (CNV) events. Although TP53 and other driver mutation genes have a high frequency in the samples, their mutation sites show significant heterogeneity in paired tumor specimens. On the other hand, CNV genes exhibited higher concordance in paired samples, especially in the amplification of oncogenes and the deletion of tumor suppressor genes.ConclusionsThe extent of inter-tumor heterogeneity suggests both monoclonal and polyclonal origins of MECC, which could provide insight into the genome diversity of MECC and guide clinical implementation.

Risk factors for cervical lymph node metastasis of papillary thyroid cancer in elderly patients aged 65 and older.

To assess the risk factors of cervical lymph node metastasis in elderly patients aged 65 years and older diagnosed with papillary thyroid cancer (PTC). In this retrospective analysis, we included a total of 328 elderly patients aged 65 years and older diagnosed with PTC. We thoroughly examined clinical features from these patients. Utilizing univariate and multivariate logistic regression analyses, we aimed to identify factors contributing to the risk of central and lateral lymph node metastasis (CLNM/LLNM) in this specific population of PTC patients aged 65 years and older. In the univariate analysis, CLNM was significantly associated with tumor size, multifocality, bilaterality, and microcalcification, while only tumor size ≥ 1cm (OR = 0.530, P = 0.019, 95% CI = 0.311 - 0.900) and multifocality (OR = 0.291, P < 0.001, 95% CI = 0.148 - 0.574) remained as risk factors in the multivariate analysis. LLNM was confirmed to be associated with male (OR = 0.454, P < 0.020, 95% CI = 0.233 - 0.884), tumor size ≥ 1cm (OR = 0.471, P = 0.030, 95% CI = 0.239 - 0.928), age ≥ 70 (OR = 0.489, P = 0.032, 95% CI = 0.254 - 0.941), and microcalcification (OR = 0.384, P = 0.008, 95% CI = 0.189 - 0.781) in the multivariate analysis. In elderly PTC patients with CLNM, male gender (OR = 0.350, P = 0.021, 95% CI = 0.143 - 0.855), age ≥ 70 (OR = 0.339, P = 0.015, 95% CI = 0.142 - 0.810), and bilaterality (OR = 0.320, P = 0.012, 95% CI = 0.131 - 0.779) were closely associated with concomitant LLNM in both univariate and multivariate analyses. For elderly PTC patients aged 65 and older, tumor size ≥ 1cm and multifocality are significant risk factors for CLNM. Meanwhile, male, tumor size ≥ 1cm, age ≥ 70, and microcalcification are crucial predictors for LLNM. In patients already diagnosed with CLNM, male, age ≥ 70, and bilaterality increase the risk of LLNM.

The Effect of Hemithyroidectomy in Papillary Thyroid Carcinoma with an Exclusive Involvement of the Recurrent Laryngeal Nerve: A Retrospective Study with a Propensity Score-Matched Analysis.

Involvement of the recurrent laryngeal nerve (RLN) in papillary thyroid carcinoma (PTC) is an important prognostic factor and is associated with a higher risk of recurrence. This study aimed to retrospectively analyze the outcomes of patients treated with hemithyroidectomy (HT) in PTC patients with an exclusive RLN invasion who could not tolerate staged surgery, did not wish to undergo another operation, or had other reasons. A retrospective review was conducted on 163 patients with PTC and exclusive RLN involvement at our institution between 2013 and 2019. Patients were divided into a total thyroidectomy (TT) group and HT group. The clinicopathologic factors and prognostic outcomes were compared between the two groups. A propensity score-matched analysis was carried out to reduce selection bias, with the following covariates: gender, age, tumor size, multifocality, central lymph node metastasis (CLNM), and RLN resection. The Kaplan-Meier method was used for a comparison of recurrence outcomes. In the baseline data of the 163 PTC patients, tumor size (p < 0.001), multifocality (p = 0.011), CLNM (p < 0.001), and RLN resection (p < 0.008) in the TT and HT groups differed significantly, whereas age and gender did not differ between the two groups. The TT group reported significantly higher temporary and permanent hypoparathyroidism than the HT group (p < 0.001 and p = 0.042, respectively). With 72-month median follow-up, 11 (6.7%) patients developed recurrence. After propensity score matching, 24 patients with HT and 43 patients with TT were included. Recurrence-free survival (RFS) in the matched samples showed no difference between the TT and HT groups (p = 0.092). Our results indicate that HT may be a feasible treatment for PTC patients with exclusive RLN involvement in specific circumstances without significantly increasing the risk of recurrence. Performing a thorough preoperative examination is crucial to exclude multifocal tumors and lymph node metastasis before undergoing HT.

Neuroblastoma Predisposition and Surveillance-An Update from the 2023 AACR Childhood Cancer Predisposition Workshop.

Genetic predisposition to neuroblastoma (NB) is relatively rare. Only 1% to 2% of patients have a family history of NB, 3% to 4% of cases present with bilateral or multifocal primary tumors, and occasional patients have syndromes that are associated with increased NB risk. Previously, a germline pathogenic variant (GPV) in PHOX2B was associated with Hirschsprung disease and congenital central hypoventilation syndrome. Recently, certain GPVs were shown to be responsible for congenital central hypoventilation syndrome and NB predisposition. Also, several groups determined that activating GPVs in ALK accounted for a substantial number of familial NB. Finally, there are additional genes and cancer predisposition syndromes in which NB occurs with greater frequency or that have been associated with NB based on genome-wide association studies. We review the evidence for all these genes and whether there is sufficient evidence to warrant surveillance. We review recommended surveillance for hereditary patients with NB, including minor updates to surveillance recommendations that were published previously in 2017.

Predictive and prognostic value of aurora kinase A combined with tumor-infiltrating lymphocytes in medullary thyroid carcinoma.

Aurora kinase A (AURKA) and tumor-infiltrating lymphocytes (TILs) are both known to play an essential role in tumorigenesis. However, the expression and prognostic value of the AURKA and TILs in medullary thyroid carcinoma (MTC) have not yet been investigated. Surgical specimens and clinical data of 137 patients diagnosed with MTC were collected. AURKA expression and TILs infiltration were quantified by immunohistochemistry and hematoxylin-eosin staining. Subsequently, the prognostic value of AURKA expression and TIL infiltration in MTC was evaluated. AURKA was highly expressed in patients with multifocal tumor, cervical lymph node metastasis, and an advanced TNM stage, indicating a high probability of recurrence. AURKA further exhibited a positive correlation with TILs (R = 0.44, P < 0.001). High expression of AURKA combined with a low numbers of TILs (AURKAhigh/TILslow) was identified as an independent prognostic factor for biochemical recurrence (odds ratio: 4.57, 95% confidence interval: 1.54-14.66, P < 0.01) and recurrence-free survival (hazard ratio: 3.64, 95% confidence interval: 1.52-8.71, P < 0.001). The combination of AURKA and TILs apparently improves the prognostic value for biochemical recurrence (area under the curve: 0.751) and structural recurrence (area under the curve: 0.836) of MTC. Notably, AURKAhigh/TILslow demonstrated a high value for prediction of distant or unresectable locoregional recurrence, with an overall accuracy of 86.9%. AURKAhigh is associated with the MTC malignancy. The combination of AURKAhigh/TILslow was identified as novel independent prognostic marker in MTC, predicting incurable disease recurrence with high accuracy.

Risk factors for positive margin in breast conservation surgery for localized breast cancer.

e12539 Background: Breast cancer is an evolving global concern due to its increasingly high morbidity and mortality rates. This is, in part, due to health care disparities in breast cancer patients that have been a problem for screening, diagnosis, and treatment. Breast-conservation surgery (BCS) is defined as the removal of breast tumor tissue surrounded by a margin of normal tissue and includes lumpectomy, partial mastectomy, wide excision, and segmental mastectomy. Negative margins post-BCS are necessary to avoid any breast cancer recurrence. A negative margin is defined as no gross or microscopic disease, also known as no tumor on ink. Positive margins are associated with patients who may have to undergo re-excisions with larger margins or total mastectomy, exposing patients to greater morbidity and delaying the start of adjuvant therapy. Methods: This was a retrospective cohort study designed to examine factors associated with positive margins (PM) in breast cancer patients undergoing breast-conserving surgery. The Charleston Area Medical Center cancer registry was queried from 2009-2022 for females diagnosed with invasive breast cancer who had surgery for localized disease (TxN0M0), excluding those with previous malignancies. Data were analyzed with SAS 9.4 using student’s t-test for continuous variables, Chi-square or Fisher’s exact for categorical variables, and multivariate analysis to identify factors predictive of positive margins. Results: In total, 1133 female patients with mean age of 64±11 met inclusion criteria. The positive margin group (PMG) made up 10.2% of the population while the negative margin group (NMG) was 89.8%. The PMG had significantly (p &lt; .0001) larger tumors than the NMG, 19.7±12 and 13.8±9, respectively. Multifocal tumors made up 18% of the PMG compared to 4.4% of the NMG (p &lt; .0001). Invasive lobular carcinoma made up 20% of the PMG compared to 7.2% of the NMG (p = .003). Recurrence was significantly (p = .030) higher in the PMG compared to the NMG, 7.4% and 3.2%, respectively; however, 5-year survival showed no difference. Regression modeling showed that multifocal tumors were 4.4 times (95% CI: 2.4-8; p &lt; .0001) more likely to be associated with PM, lobular carcinoma was 2.8 times (95% CI: 1.6-4.8; p = .0003) more likely to be associated with PM, and stage II patients were 2.4 times (95% CI: 1.5-3.7; p = .0002) more likely to have PM. Conclusions: Univariately, tumor size, multifocality, lobular carcinoma, stage II, and local/distant recurrence were all associated with positive margins. This finding was re-demonstrated with respect to multifocality, lobular carcinoma, and stage II following multivariate analysis. The results of this study may help to guide surgeons and oncologists in the management of localized, invasive breast cancer, especially in emphasizing the importance of timely follow-up in patients at higher risk and in the education of patients regarding their care.

Early experience with sequential intravesical gemcitabine and docetaxel for micropapillary variant non-muscle invasive bladder cancer

BackgroundGuidelines lack clear recommendations regarding conservative management of micropapillary (MP) variant non-muscle invasive bladder cancer (NMIBC). Bladder-sparing therapy using intravesical Bacillus Calmette-Guerin (BCG) has been reported although there are concerns regarding recurrence and progression with this approach. Due to the ongoing BCG shortage, we have utilized sequential intravesical gemcitabine and docetaxel (Gem/Doce) as primary therapy for NMIBC, including some cases with limited MP urothelial carcinoma (MPUC). To compare oncologic outcomes of patients with non-muscle invasive MPUC and conventional UC treated with Gem/Doce. MethodsA secondary analysis of 138 patients with high-risk NMIBC treated with intravesical Gem/Doce from January 2011 to December 2021 was performed. Oncologic outcomes were compared in patients with or without MPUC using the Kaplan-Meier method. ResultsMedian follow-up (f/u) for all patients was 23 months (IQR 13–34). There were 129 patients with pure UC and 9 with MPUC. In those with MPUC, all were high-grade (HG), 8/9 were stage T1, 7/9 had a focal MP component (extent < 10%), 3/9 had concomitant CIS, and 2/9 had lymphovascular invasion. All MPUC tumors were re-resected, and 4 had T0, 3 had T1 HG, 1 had Ta HG, 1 had carcinoma in situ (CIS); none had residual MP or LVI tumors before Gem/Doce treatment. The 24-month high-grade recurrence-free survival was 89% and 80% in patients with MPUC and pure UC, respectively. Survival outcomes did not significantly differ between patients with and without MPUC. Four patients with MPUC experienced recurrent NMIBC after Gem/Doce, and all were treated successfully with rescue sequential intravesical valrubicin and docetaxel (Val/Doce). Pathology of these four recurrent patients revealed more aggressive histologic features in the original tumor including: multifocal tumor (3/4), T1 HG disease (4/4), concomitant CIS (2/4), and moderate MP variant extent (30%) (1/4). No patient with MPUC underwent cystectomy, experienced progression, or died at last follow-up (median f/u of 43 months). ConclusionsGem/Doce with Val/Doce rescue appears to have activity against carefully selected non-muscle invasive MPUC with favorable histology. Larger prospective trials are needed to validate these results.

Interplay of metabolic dysfunction-associated fatty liver disease and papillary thyroid carcinoma: insights from a Chinese cohort.

Thyroid cancer is one of a set of extrahepatic cancers that closely linked to metabolic dysfunction-associated fatty liver disease (MAFLD). However, the connection between MAFLD and the characteristics of papillary thyroid cancer (PTC) remains unexplored. Between Jan 2020 and Oct 2022, surgical cases of PTC patients were examined at the first Affiliated Hospital of Wenzhou Medical University. Clinical data extracted from the electronic medical system underwent a rigorous comparison between two groups, classified based on MAFLD criteria, using logistic regression analysis. In this study of 4,410 PTC patients, 18.3% had MAFLD. MAFLD emerged as a distinct risk factor for lymph node metastasis (OR = 1.230, 95% CI 1.018-1.487) in this cohort, especially in females (OR = 1.321, 95% CI 1.026-1.702) and those with BMI ≥ 23kg/m2 (OR = 1.232, 95% CI 1.004-1.511). The presence of MAFLD was found to significantly elevate the risk of BRAF V600E mutation in both subgroups characterized by FIB-4 score ≥ 1.3 (OR = 1.968, 95% CI 1.107-3.496) and BMI < 23kg/m2 (OR = 2.584, 95% CI 1.012-6.601). Moreover, among the subset of individuals without non-alcoholic fatty liver disease (NAFLD), it was noted that MAFLD considerably increased the likelihood of tumor multifocality (OR = 1.697, 95% CI 1.111-2.592). Nevertheless, MAFLD did not exhibit any correlation with increased tumor size, extra-thyroidal extension (ETE), or later TNM stage in PTC. In this cross-sectional study, we discovered a significant association between MAFLD and increased occurrences of lymph node metastasis. Furthermore, MAFLD was linked to a higher chance of BRAF V600E mutation and the presence of multiple tumors in certain subgroups.

Abstract A023: Stratification of bladder cancer patients with the use of flow cytometry is increasing the diagnostic potential of molecular classifiers

Abstract Recent research suggests the potential categorization of bladder cancer (BLCa) patients into molecular subtypes to aid in the selection of appropriate treatment strategies, be it conventional, targeted, or a combination thereof. However, the practical implementation of molecular classifiers has faced obstacles due to the intricate nature of gene regulation, tumor heterogeneity, and challenges related to tumor sampling caused by substantial stromal infiltration and tumor multifocality. Hence, there is a pressing need for more straightforward marker-based methodologies to assist in genomic and transcriptomic subtyping efforts. Our study addressed this gap by establishing and validating a panel of antibodies for application in flow cytometry (FCM) to enhance the stratification of BLCa patients. We curated a set of 17 FCM markers capable of delineating four cell clusters (epithelial, immune, endothelial, and stromal) and defining tumor classification (basal and luminal), immune infiltration, and hot-target expression on BLCa tissue samples. This FCM panel was deployed on ex vivo tissue samples treated with chemotherapy and targeted therapy agents. Initially tested on a cohort of 10 BLCa tissue samples, our validation of the FCM panel revealed correlations between marker expression and clinical-pathological features, such as the presence of metastasis and heightened immune and stromal infiltration. Notably, samples exhibiting lower claudin-4 levels displayed increased immune infiltration, while those with metastases at diagnosis showcased elevated basal marker expression. The translational potential of the FCM panel was demonstrated in ex vivo experiments where tissue slices from six patients were subjected to chemotherapy and targeted therapy agents, leading to observable shifts in marker expression post-treatment, particularly pronounced with chemotherapy. Noteworthy effects included reductions in epithelial cells expressing FGFR3 and EGFR following targeted therapy with erdafitinib or lapatinib, alongside alterations in the basal/luminal cell ratio indicated by increased CD44, CD90, and CD239 marker expressions. Our findings underscore the value of FCM in categorizing BLCa patients based on specific marker expression, supplementing conventional histological analyses to enhance cancer diagnosis, guide personalized therapeutic approaches, and monitor treatment efficacy. Citation Format: Martina Radic, Federico La Manna, Martina Minoli, Panagiotis Chouvardas, George N. Thalmann, Roland Seiler-Blarer, Marianna Kruithof-de Julio, Bernhard Kiss. Stratification of bladder cancer patients with the use of flow cytometry is increasing the diagnostic potential of molecular classifiers [abstract]. In: Proceedings of the AACR Special Conference on Bladder Cancer: Transforming the Field; 2024 May 17-20; Charlotte, NC. Philadelphia (PA): AACR; Clin Cancer Res 2024;30(10_Suppl):Abstract nr A023.

Synchronous Ewing sarcoma of the fibula with involvement of the orbit and abducens nerve palsy

Simultaneous or synchronous Ewing sarcoma (ES) is the occurrence of multifocal lesions without pulmonary involvement. This is a very rare condition. We present a case of multifocal synchronous ES of the fibula with orbital involvement and adducens nerve palsy. A 17-year-old boy presented with pain and swelling in both legs for 6 weeks. He was unable to walk due to pain. He was pale and cachexic. There was proptosis and ptosis in the right eye. His investigations were consistent with a multifocal malignant tumor. There were lesions in the left fibula, tibia, right tibia, and right orbit. The histopathological diagnosis was Ewing sarcoma (ES). This is the first report of synchronous ES involving the orbit and abducens nerve.

The significance of BAP1 and MTAP/CDKN2A expression in well-differentiated papillary mesothelial tumour: a series of 21 cases and a review of the literature

The nomenclature and diagnostic criteria of well-differentiated papillary mesothelial tumour (WDPMT) have been changed in the 2021 World Health Organization (WHO) classification of thoracic tumours, and a new entity, mesothelioma in situ (MIS), introduced. Histologically these two entities may be similar. However, MIS is regarded as a precursor to invasive mesothelioma and requires demonstration of loss of BAP1 and/or MTAP/CDKN2A for diagnosis, whereas performance of these ancillary tests is desirable but not essential for a diagnosis of WDPMT, in which the significance of BAP1 and/or MTAP/CDKN2A loss is not well understood or well defined. Against this backdrop, we undertook an investigation of 21 cases of WDPMT, identified from our case files and diagnosed according to 2021 WHO criteria, to explore the relationship between histology and BAP1 and MTAP/CDKN2A expression with clinical features including asbestos exposure, focality of tumours and clinical outcome. There were 18 women and three men, with ages ranging from 23-77 years (median 62 years), in which six had a history of asbestos exposure, two had no exposure, and in 13 exposure history was unavailable. Of 20 peritoneal tumours and one pleural tumour, 13 were detected incidentally at the time of surgery for unrelated conditions and eight peritoneal tumours were multifocal at the time of diagnosis. BAP1 immunohistochemistry (IHC) was performed in all 21 tumours, with nine tumours showing BAP1 expression loss. MTAP/CDKN2A testing was performed in 14 tumours, comprising MTAP IHC in 12 and CDKN2A fluorescence in situ hybridisation (FISH) in two, with three tumours showing MTAP/CDKN2A expression loss. Two tumours with MTAP/CDKN2A loss also showed BAP1 expression loss. Four patients progressed to invasive mesothelioma, including one male with a pleural tumour and asbestos exposure, and three females with multifocal peritoneal tumours, two with asbestos exposure and one without exposure. BAP1 expression loss was seen in all tumours from the four patients who progressed to invasive mesothelioma, whilst two of these tumours showed retained MTAP IHC and two were not tested. There was one patient with a tumour with MTAP loss and retained BAP1 who died from unrelated causes 5 months after diagnosis. Eight patients received WDPMT-specific treatment in addition to the initial excision. Survival for all patients ranged from 4-218 months, with one patient dying of mesothelioma at 49 months. Based on our results in this series of 21 patients with WDPMT diagnosed according to 2021 WHO criteria, we propose that WDPMT with BAP1 expression loss may best be regarded as papillary MIS and that a history of asbestos exposure and the presence of multifocal tumours in patients diagnosed with WDPMT should prompt ancillary testing with BAP1 IHC. Further we propose that BAP1 IHC should be essential in the diagnosis of WDPMT, with the diagnosis restricted to those tumours which show retained BAP1 expression. However more studies in larger cohorts of patients are needed to explore the relationship between BAP1 expression and MTAP loss in WDPMT, which will help to define this entity and separate it more clearly from MIS and invasive mesothelioma.

From Morphology to Molecules: Advances in the Distinction of Multiple Primary Lung Cancers From Intrapulmonary Metastases in Non-Small Cell Lung Cancer.

The increasing incidence of multiple lung nodules underscores the need for precise differentiation between multiple primary lung cancers (MPLCs) and intrapulmonary metastases (IPMs). This distinction impacts patient prognosis and treatment strategies. The prevalence of multiple lung nodules, ranging from 19.7% to 55.5%, highlights the clinical significance of this challenge. Historically, the role of histopathology, particularly comprehensive histology assessment (CHA), has been pivotal in differentiating MPLCs and IPMs. However, CHA has significant limitations, resulting in a constant search for a better way to distinguish those lesions. The best strategy for delineating MPLCs from IPMs is a multidisciplinary approach combining clinical data, radiology, histology, and molecular methods. Histology provides architectural and cellular characteristics, radiology contributes anatomic context and lesion characterization, and molecular methods reveal molecular features critical for accurate differentiation. Incorporating clinical data further enhances diagnostic precision. This review presents current knowledge and current approaches to multiple lung tumors. It is clear that even with a combination of pathology, radiology, and molecular data, definitive classification of multifocal lung tumors is not always possible.

Classification of multiple primary lung cancer in patients with multifocal lung cancer: assessment of a machine learning approach using multidimensional genomic data.

Multiple primary lung cancer (MPLC) is an increasingly well-known clinical phenomenon. However, its molecular characterizations are poorly understood, and still lacks of effective method to distinguish it from intrapulmonary metastasis (IM). Herein, we propose an identification model based on molecular multidimensional analysis in order to accurately optimize treatment. A total of 112 Chinese lung cancers harboring at least two tumors (n = 270) were enrolled. We retrospectively selected 74 patients with 121 tumor pairs and randomly divided the tumor pairs into a training cohort and a test cohort in a 7:3 ratio. A novel model was established in training cohort, optimized for MPLC identification using comprehensive genomic profiling analyzed by a broad panel with 808 cancer-related genes, and evaluated in the test cohort and a prospective validation cohort of 38 patients with 112 tumors. We found differences in molecular characterizations between the two diseases and rigorously selected the characterizations to build an identification model. We evaluated the performance of the classifier using the test cohort data and observed an 89.5% percent agreement (PA) for MPLC and a 100.0% percent agreement for IM. The model showed an excellent area under the curve (AUC) of 0.947 and a 91.3% overall accuracy. Similarly, the assay achieved a considerable performance in the independent validation set with an AUC of 0.938 and an MPLC predictive value of 100%. More importantly, the MPLC predictive value of the classification achieved 100% in both the test set and validation cohort. Compared to our previous mutation-based method, the classifier showed better κ consistencies with clinical classification among all 112 patients (0.84 vs. 0.65, p <.01). These data provide novel evidence of MPLC-specific genomic characteristics and demonstrate that our one-step molecular classifier can accurately classify multifocal lung tumors as MPLC or IM, which suggested that broad panel NGS may be a useful tool for assisting with differential diagnoses.

Abstract PO5-02-07: Multifocal breast cancer: tumor biology and prognostic importance

Abstract &amp;gt;Multifocal breast cancer: tumor biology and prognostic importance Background The incidence of multifocal breast cancer (MBC) varies widely in the literature and recent reports indicate that the incidence of MBC is increasing. Several studies have shown similar tumor biology in the different foci of multifocal tumors, and it has been suggested that multifocal tumors may in fact be intramammary metastases and thus be a sign of a more aggressive cancer type than unifocal tumors. Knowledge regarding outcome and optimal treatment of MBC compared to unifocal breast cancer (UBC) is still limited. The aim of the present study was to explore if multifocal breast cancers have less favorable characteristics and prognosis compared to unifocal breast cancers. Method Patient and tumor characteristics were obtained from Breast Cancer database Sweden (BcBaSe3) including women with invasive breast cancer 2008-2019 who had undergone primary surgery. Women with distant metastases at time of diagnosis, women receiving neoadjuvant systemic therapy, and men were excluded. Overall- and breast cancer specific survival were calculated with Kaplan-Meier and Cox-regression analyses. Results A total of 71607 women met our inclusion criteria, 11961 (16.7%) with MBC and 59512 (83.3%) with UBC. Among women with MBC, 64.1% underwent mastectomy compared to 32.4% of women with UBC and 40.1% with MBC underwent complete axillary lymph node dissection compared to 23.5% of the women with UBC. MBC was associated with higher T-stage (T2 31.9% vs. 25.8% and T3 4.6% vs. 2.6%. p&amp;lt; 0.001) and higher N-stage (N+ 13.7% vs. 8.4%, P&amp;lt; 0.001), compared to UBC. MBC were more often of lobular type (18.8% vs. 12.4%, P&amp;lt; 0.001), of higher grade (grade 3 29.3% vs. 27.3%, p&amp;lt; 0.001), with positive hormone receptor status (88.4% vs. 86.7%, p&amp;lt; 0.001), and Her2 positivity (13.3% vs. 10.9%, p&amp;lt; 0.001). Adjuvant systemic treatment was more frequently administered to women with MBC, adjuvant chemotherapy (45.3% vs. 33.3%, p&amp;lt; 0.001) and endocrine treatment (82.9% vs. 75.3%, p&amp;lt; 0.001). Breast cancer specific 10- year survival was 86.4% and 88.5% for MBC and UBC respectively, hazard ratio for breast cancer death 1.19 (95 % confidence interval, 1.11- 1.28). Overall survival did not differ between the two groups (10-year survival 76.0%, p=0.35) Conclusion MBC appears to have a more aggressive tumor biology than UBC, with the exception of hormone receptor status and MBC is associated with decreased breast cancer specific survival. Further analysis of possible interactions with different treatment methods will be conducted. Citation Format: Emma Söderberg, Malin Sund, Fredrik Wärnberg, Hans Garmo, Anna-Karin Wennstig, Lars Holmberg, Greger Nilsson, Charlotta Wadsten. Multifocal breast cancer: tumor biology and prognostic importance [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO5-02-07.

Abstract PO5-18-10: Omission of SLNB in triple-negative and HER2-positive breast cancer patients with radiologic and pathologic complete response in the breast after NAST: a single-arm, prospective surgical trial (EUBREAST-01 trial, GBG 104)

Abstract Background: Currently, axillary surgery for breast cancer is considered a staging procedure that does not seem to influence breast cancer mortality since the risk of developing metastasis depends mainly on the biological behavior of the primary (seed-and-soil model). Based on this, postsurgical therapy should be considered based on biological tumor characteristics. Retrospective data of cancer registry trials showed a strong correlation between breast pathologic complete response (pCR) and nodal pCR depending on intrinsic subtypes. Improvements in systemic treatments for breast cancer have increased the rates of pCR in patients receiving neoadjuvant systemic therapy (NAST), offering the opportunity to decrease, and perhaps eliminate, surgery in patients who have a pCR. Trial design: The EUBREAST network designed a clinical trial (NCT04101851) in which only patients with the highest likelihood of having a pCR after NAST (triple-negative or HER2-positive breast cancer) will be included, and type of surgery will be defined according to the response to NAST rather than on the classical T and N status at presentation. In the ongoing trial, axillary surgery will be eliminated (no axillary sentinel lymph node biopsy [SLNB]) for initially clinical node-negative (cN0) patients with radiologic complete remission (rCR) and a breast pCR (ypT0/ypTis) as determined in the lumpectomy specimen. The trial design is a multicenter single-arm study with a limited number of patients (N=440 as the screening population with an expected 80% pCR-rate) which might give practice-changing results in a short period, sparing the time and the costs of a randomized comparison. Patients will be recruited in European countries (Austria, Germany, Italy, and Spain) over 48 months. Inclusion criteria: -Written informed consent -Histologically confirmed unilateral primary invasive carcinoma of the breast (core biopsy). Multifocal or multicentric tumors are allowed if breast-conserving surgery (BCS) is planned. -Age at diagnosis at least 18 years -imaging techniques with estimated tumor stage between cT1-T3 before NAST -triple-negative (TNBC) or HER2-positive invasive breast cancer -TNBC is defined by: ER-negative (&amp;lt; 10% positive cells in IHC) and PgR-negative (&amp;lt; 10% positive cells in IHC), HER2-negative -clinically and sonographically tumor-free axilla before core biopsy (cN0/iN0) -in cases with cN0 and iN+, a negative core biopsy or fine-needle aspiration biopsy of the sonographically suspected lymph node is required -no evidence for distant metastasis (M0) -standard NAST with rCR -planned BCS with postoperative external whole-breast irradiation (conventional fractionation or hypofractionation) Primary objective: 3-year rate of axillary recurrence-free survival (ARFS) after BCS Statistics: The calculated total case number for per-protocol analysis is N=350, and the expected total number of screened patients is N=440. The assumption for acceptable 3-year ARFS ≥98.5% in the experimental arm is based on previous study findings. Timelines: -First patient in: January 2021 -Last patient in: December 2024 -Primary outcome analysis: Q1/2027 Current accrual: In June 2023, 255 patients were recruited; the majority of them in Germany. Contact: Prof. Dr. Toralf Reimer (eubreast-01@kliniksued-rostock.de), study chair Dr. Oreste D. Gentilini (gentilini.oreste@hsr.it), study co-chair Funding by Else Kroener-Fresenius Foundation, German Society of Senology, University of Rostock (Germany), and San Raffaele Hospital (Milan, Italy). Citation Format: Toralf Reimer, Bernd Gerber, Thorsten Kuehn, Nikola Bangemann, Anke Kleine-Tebbe, Andrea Stefek, Ulrike Doerste, Carolin Hammerle, Oliver Hoffmann, Alexander Hein, Isabel Rubio, Florentia Peintinger, Keyur Mehta, Sibylle Loibl, Edoardo Botteri, Oreste Gentilini. Omission of SLNB in triple-negative and HER2-positive breast cancer patients with radiologic and pathologic complete response in the breast after NAST: a single-arm, prospective surgical trial (EUBREAST-01 trial, GBG 104) [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO5-18-10.

Abstract PO5-20-08: A Case of Multifocal Ductal Breast Carcinoma with Extension into Lobules and Concurrent Primary Colon Adenocarcinoma

Abstract Background Multifocal (MF) multicentric breast cancer is a form of breast cancer that consists of disease independently developing at various locations due to a tumor clone spreading within the ductal complex. Multifocal breast cancer is associated with increased local recurrence. Our case highlights an example of multifocal breast cancer and addresses treatment challenges. Case presentation The patient is a 52-year-old African American female with a history of HCV cirrhosis, diabetes mellitus, and hypertension who presented with a palpable 4 cm right breast mass, without adenopathy, clinically Stage II, T2N0. Mammogram revealed a 2.5 cm right breast mass and three right level 1 axillary nodes with biopsy confirming invasive ductal carcinoma with extension into the lobules, ER positive (3%)/PR-/HER2-, Ki-67 95%. Neoadjuvant paclitaxel, carboplatin, and pembrolizumab was initiated but she incurred complications of decompensated liver cirrhosis after the second cycle and treatment was held. After 2 cycles her tumor was not palpable, and surgery was recommended, but due to COVID infection and concurrent decompensated liver failure surgery management was delayed. She underwent staged surgery with partial mastectomy without lymph node exploration. Histopathology showed DCIS grade 3 with extension into lobules and invasive ductal carcinoma with no lymphovascular invasion and all margins were negative, pathological stage ypT3NxM0. Immunohistochemistry demonstrated partial ER+ (50%)/PR-/HER2-, Ki-67 80%. She was given 4 cycles of adjuvant cyclophosphamide, adriamycin, pembrolizumab and continued on maintenance pembrolizumab. The patient was found with anemia out of proportion to chemotherapy and underwent colonoscopy that showed a colonic mass. Biopsy showed a primary moderately differentiated colonic adenocarcinoma. Her re-excision with new margins for partial mastectomy had negative margins, and 2 negative sentinel lymph nodes for ypN0. Genetic testing was negative. She continued on adjuvant immunotherapy with pembrolizumab for breast cancer. She is planned to start on adjuvant anastrozole. Patient has completed adjuvant radiation treatment and has no new complaints. She is pending curative intent completion colectomy for colon cancer. Discussion This case of MF breast cancer is significant, as one foci was ER negative, which responded to neoadjuvant chemoimmunotherapy and other ER positive that did not respond to treatment and was surgically excised. The pathology report from the surgical specimen revealed DCIS with extension into the lobules. Due to her tenuous clinical condition, she had staged surgeries for breast cancer, and now colon cancer. Genetic testing is negative. Currently, there is insufficient data to suggest which surgical approach is preferred in MF breast cancer. Based on the literature, breast conservation therapy (BCT) is a feasible option and is oncologically safe. Due to the patients’ medical condition and infections, it was felt a less invasive surgery could offer cure and minimize complications. Our patient underwent neoadjuvant chemoimmunotherapy, followed by partial mastectomy, adjuvant chemoimmunotherapy, second staged completion breast surgery, radiation therapy, and anti-estrogen therapy. MF breast cancer is associated with increased lymph node involvement. A 2022 meta-analysis found that multifocal and multicentric breast cancer has a slightly increased risk of death as compared to unifocal tumors. Lastly, our patient is African American, and multifocal tumors occur with a higher incidence in African Americans (43.4%) and Asian patients (37%) as compared to whites (28.9%). This case of breast cancer highlights treatment challenges in a case of multifocal multicentric breast cancer occurring concurrently with a secondary primary colonic cancer. Citation Format: Rabab Jafry, Hina Khan, Jessica Jones. A Case of Multifocal Ductal Breast Carcinoma with Extension into Lobules and Concurrent Primary Colon Adenocarcinoma [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO5-20-08.