Main Clinicopathological Features Research Articles

18F-Fluorodeoxyglucose Uptake in PDGFRA-Mutant Gastrointestinal Stromal Tumors

The D842V platelet-derived growth factor receptor α (PDGFRA) mutation identifies a molecular subgroup of gastrointestinal stromal tumors (GISTs), primarily resistant to standard tyrosine kinase inhibitors and with an overall more indolent behavior. Although functional imaging with 18F-fluorodeoxyglucose-labeled positron emission tomography ([18F]FDG-PET) plays a proven role in GISTs, especially in early assessment of tumor response, less is known about [18F]FDG uptake according to the GIST molecular subtypes. To evaluate the degree of [18F]FDG uptake in PDGFRA-mutant GISTs and better define the role of functional imaging in this rare and peculiar subset of GISTs. This multi-institutional retrospective cohort study involving 7 GIST reference centers in Italy included patients with PDGFRA-mutant GIST who underwent [18F]FDG-PET from January 1, 2000, to December 31, 2023. Data on the maximum standardized uptake value (SUVmax) of primary tumor or metastatic disease were collected. PDGFRA-mutant GIST and [18F]FDG-PET. The primary outcome was the degree of [18F]FDG uptake of PDGFRA-mutant GISTs, with a focus on the D842V-mutant subgroup. Secondary objectives were to assess the association between the degree of [18F]FDG uptake and main clinicopathologic features. A total of 71 patients with PDGFRA-mutant GISTs were included in the analysis: 37 (52.1%) in the D842V subgroup (group A) and 34 (47.9%) in the non-D842V subgroup (group B). Additionally, 70 patients with KIT exon 11-mutant GIST served as a control group (group C). For all 141 participants, the median age at diagnosis was 59 (range, 26-89) years, and 81 patients (57.4%) were male. Overall, the median SUVmax was 4.4 (IQR, 0-10.1), while the median SUVmax for group A was 0 (IQR, 0-3.2); for group B, 3.6 (IQR, 0-5.1); and for group C, 10.1 (IQR, 5.1-13.9). The median SUVmax of PDGFRA-mutant GISTs was significantly lower than the median value of KIT exon 11-mutant GISTs (0 [IQR, 0-4.3] vs 10.1 [IQR, 5.1-14.0]; P < .001). Median [18F]FDG uptake was significantly lower in the D842V subgroup compared with the non-D842V subgroup (0 [IQR, 0-3.2] vs 3.6 [IQR, 0-5.1]; P = .02). Moreover, the triad of gastric primary tumor, tumor size greater than 10 cm, and SUVmax of 5.75 or less was associated with identification of PDGFRA-mutant GISTs. In this cohort study of patients with PDGFRA-mutant GISTs, the D842V-mutant GISTs were associated with an overall lower [18F]FDG uptake compared with other GIST subgroups. Therefore, the role of functional imaging with [18F]FDG-PET in this subset of GISTs may be limited and should be further explored for its potential prognostic and predictive value.

Identifying predictors of treatment response and molecular changes induced by neoadjuvant chemotherapy and endocrine therapy in hormone receptor-positive/HER2-negative breast cancer: the NEOENDO translational study

Predictors of response to neoadjuvant chemotherapy (NACT) and endocrine therapy (NET) in hormone receptor-positive (HoR+)/human epidermal growth factor receptor 2 (HER2)-negative breast cancer (BC) are required. Also, pathological and molecular changes induced by both strategies and their impact on patients' outcomes have not been reported so far. In a cohort of 186 patients with early-stage HoR+/HER2-negative BC treated with NACT or NET, we assessed the association of baseline main clinicopathological features and PAM50 gene expression (GE), intrinsic subtypes (IS) and risk-of-relapse (ROR-P) score with pathological outcomes according to treatment strategy. Molecular NACT/NET-induced changes were described and compared, along with their associations with event-free survival (EFS). Comparison of the two cohorts after propensity score matching (PSM) was used as sensitivity analysis. Molecular changes were confirmed in cell lines. NACT was associated with higher rates of residual cancer burden (RCB)-0/I than NET in the overall population (38.2% versus 13.5%, P < 0.001) and after PSM (P= 0.036). PAM50 non-luminal IS were the only independent and positive predictor of RCB-0/I (P= 0.024) in the NACT cohort, while MMP11 messenger RNA levels were the only independent and negative predictor (P= 0.014) in the NET cohort. Both treatments shifted the tumor types toward less aggressive forms (i.e. PAM50 luminal A/normal-like), lowered the risk of recurrence in terms of ROR-P, up-regulated selected immune genes and PAM50 basal-like-related genes/signature and significantly downregulated proliferation-/luminal-/HER2-related genes/signatures, though NACT more than NET. Molecular findings were confirmed after PSM. A net reduction in proliferation-related genes and ROR-P was confirmed in cell lines with chemotherapy and endocrine therapy. Different baseline molecular features associated with diverse kind of responses (ROR-P downstaging, Ki67 reduction or pathological responses) with NACT and NET. Decreasing ROR-P and transitioning the tumor subtype to resemble normal tissue (i.e. PAM50 normal-like) suggested improved EFS. NACT was more effective in the molecular and dimensional tumor 'downstaging' than NET but baseline molecular features associated with differential responses according to treatment strategy. Examining baseline and post-treatment GE might help tailor more personalized and effective care.

Abstract 900: Development and validation of an artificial-intelligence-based pathomics biomarker to predict resistance to first-line treatment in metastatic colorectal cancer

Abstract Background: The backbone chemotherapy of first-line standard of care (SOC) for microsatellite stable (MSS) metastatic colorectal cancer (mCRC) combines 5-Fluorouracil to oxaliplatin and/or irinotecan. There are no biomarkers to predict response, which is complete or long-lasting (CR/LLR) in 20-25% of patients, while 10-15% are primary refractory. The aim of this work is to develop a predictive biomarker, based on digital pathology images, that can help stratify patients according to their risk of resistance. Methods: We trained a supervised bag-of-words artificial intelligence (AI)-based model on a cohort of response outliers mCRC patients classified as “really sensitive” (RS) if they achieved CR or LLR &amp;gt;10 months to any SOC, or “really resistant” (RR) if progression occurred at first disease reassessment. Whole-slide Imaging (WSI) of the resected primary tumors were tiled into patches of 224 × 224 pixel (0.5μm/pixel). First-order and texture features were subsequently extracted from all tumoral tiles and grouped into homogenous clusters through a k-means algorithm (k=6). For each patient, the percentage of tiles belonging to each tiles’ cluster was computed to represent new features (called bag of words) with whom different machine learning classifiers were trained. Main clinicopathological features were matched to treatment response by Fisher’s exact test. Results: To date, we analyzed 82 response outlier patients, of whom 35 were classified as RS and 46 RR. Of them, patients identified at Italian centers were used as construction cohort (N=47; 27 RR and 20 RS) and those identified at Spanish centers were used a validation cohort (N=35; 19 RR and 16 RS). The best result was obtained using a stepwise logistic regression, reaching a negative predictive value (NPV) of 90% (18/20; 95% CI=70-97%) and 71% (10/14; 95% CI=49-87%), in the construction and validation sets. No standard clinicopathological features (including stage, RAS/BRAF status, histology and sidedness) was associated with the chance of being RR. Conclusions: We demonstrated that a pathomics signature has the potential to predict resistance to SOC in MSS mCRC. Further validation of these preliminary findings on a larger cohort of response outlier patients is ongoing. Citation Format: Luca Lazzari, Gianluca Mauri, Valentina Giannini, Debora Cafaro, Giulia Nicoletti, Caterina Marchiò, Andrea Sartore-Bianchi, Federica Marmorino, Maria Nieva Munoz, Nadia Saoudi Gonzalez, Alberto Puccini, Chiara Cremolini, Clara Montagut, Elena Elez, Stefania Sciallero, Enrico Berrino, Martina Carullo, Pietro Paolo Vitiello, Maria Costanza Aquilano, Martina Di Como, Emanuela Bonoldi, Salvatore Siena, Alberto Bardelli, Daniele Regge, Silvia Marsoni. Development and validation of an artificial-intelligence-based pathomics biomarker to predict resistance to first-line treatment in metastatic colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 900.

#5081 THE VALUE OF ANTI-C1Q ANTIBODIES IN PREDICTING THE CLINICAL-HISTOLOGICAL FEATURES OF LUPUS NEPHRITIS PATIENTS AT TIME OF KIDNEY BIOPSY

Abstract Background and Aims Systemic lupus erythematosus (SLE) is a chronic autoimmune disease with renal involvement in around 50% of patients. Delayed diagnosis of lupus nephritis (LN) is associated with higher risk of end-stage kidney disease (ESKD) and mortality. Kidney biopsy remains the gold standard for diagnosis and management of LN, but in the last decades there is an interest for new serum biomarkers. Anti-C1q antibodies are autoantibodies associated with LN. Nevertheless, few studies have correlated the association of anti-C1q antibodies with active LN with focus on renal histology. Method We evaluated clinical and histological data of 59 patients with biopsy proven LN. Kidney biopsies were categorized following the ISN/RNP Classification. We evaluated the correlation of the main clinicopathologic features with values of antiC1q antibodies, measured by a commercial kit with a clinically validated ELISA test. Normal values of antiC1q were &amp;lt; 20 UA, medium values were between 20 and 80 UA and high values were &amp;gt; 80 UA. Demographic and clinical data were expressed as numbers or percentage for discrete variables and for continuous variables as mean and standard deviation. The correlation between antiC1q levels and clinicopathological characteristics have been analyzed with Fisher's test. Results At the presentation of 59 patients with LN, the mean age was 34 years and the time of SLE disease before the onset of LN was 73.2 months. 9 patients were male, mean serum creatinine was 1 mg/dl, glomerular filtration rate (eGFR) was 88.53 ml/min, proteinuria was 4.35 g/day and microscopic hematuria was present in 79% of pts. Kidney biopsies were classified as non-proliferative (class II and V) in 18.4% of patients and proliferative (class III and IV) in 77.6% of patients. We evaluated the correlation between all variables included in Table 1 with values of antiC1q antibodies and we found significant results for serum creatinine, active urinary sediment, C3 and C4 values, proliferative classes and the activity index at kidney biopsy (Table 2). Conclusion High titles of anti-C1q antibodies were significantly correlated with the main clinical and histological characteristics that identify active renal diseases in SLE. Kidney biopsy remains the gold standard for diagnosis and management of LN, but anti-c1q antibodies are strongly associated with active LN in SLE. In conclusion, anti-C1q monitoring should be helpful and might be a crucial serum biomarker for the diagnosis and follow-up of these patients.

Teratocarcinosarcoma of the head and neck: Clinicopathologic review of a rare entity.

Teratocarcinosarcoma is a rare, highly aggressive malignancy of the head and neck, characterized by multiphenotypic and triphasic growth of epithelial, mesenchymal, and primitive neuroepithelial elements. Owing to its rarity and morphological heterogeneity, as well as the lack of experience with this neoplasm, teratocarcinosarcoma is often misdiagnosed, particularly in small biopsy samples when only some of the elements are identified, thus leading to delayed management. Aggressive clinical behavior and poor survival outcomes, necessitate an accurate diagnosis and appropriate treatment. This review describes the main demographic and clinicopathological features of teratocarcinosarcoma, with an emphasis on the recent advances that have attempted to identify the molecular signature of this neoplasm.

Abstract P2-23-16: Clinico-Pathological and Molecular Characterization of HER2-Enriched Breast Tumors Independently of HER2 Status

Abstract INTRODUCTION: Breast cancer (BC) is a highly prevalent and heterogeneous disease, entailing different so-called intrinsic subtypes (IS) according to gene expression, namely Luminal A, Luminal B, HER2-Enriched (HER2E) and Basal-like, as well as a normal breast-like group. The HER2E is still a poorly understood entity, which needs further biologic characterization to improve therapeutic management. MATERIAL AND METHODS: Patients (pts) treated at Hospital Clinic (Barcelona, Spain) over 18 years with a diagnosis of metastatic BC, with available matched primary and metastatic tumor samples for gene expression analyses were retrospectively recruited. Using the nCounter® Breast Cancer 360 panel, we studied the expression of 776 genes pertaining to different tumor and immune pathway-related signatures, with a focus on HER2E vs. non-HER2E tumors. Significant changes were considered at a false discovery rate (FDR) &amp;lt; 5%. Main clinicopathological features were also compared. IS changes from primary to metastatic disease were assessed. RESULTS: Ninety-one pts with paired tumor samples were included. Briefly, primary tumors were 67.0% hormone receptor-positive (HR+)/HER2-negative (HER2-), 14.8% were HER2-positive (HER2+) and 18.2% were triple-negative (TNBC). IS distribution in primary tumors was the following: 25 Luminal A (28%), 22 Luminal B (24%), 24 HER2E (26%), 12 Basal-like (13%), and 8 Normal-like (9%). In contrast, IS distribution in metastatic tumors was the following: 13 Luminal A (14%), 22 Luminal B (24%), 34 HER2-E (37%), 16 Basal-like (18%), and 6 Normal-like (7%). The HER2E disease proved to be a relatively stable subtype, with 16 (66.7%) tumors not changing IS in the transition to metastatic disease (p=0.078). Particularly, within HR+/HER2-, HER2+ and TNBC, 8/12 (66.7%), 8/10 (80.0%) and 1/2 (50.0%) tumors remained HER2E. Conversely, an overall significant switch from Luminal to non-Luminal tumors at the metastatic progression was observed (p=0.031), with 14/19 (73.7%) new non-Luminal BC being HER2E. When considering all primary and metastatic tumors, HER2E were observed to be less frequently estrogen receptor (ER) positive than non-HER2E tumors (55.8% vs. 78.7%; p=0.002), with lower mean progesterone receptor (PR) levels (15.3% vs. 25.8%; p=0.027). Compared to the other subtypes (as a group), the PAM50 risk of recurrence score (ROR-P) was higher for HER2E tumors (59.1 vs. 41.7; p &amp;lt; 0.001), which were also more frequently HER2+ (36.5% vs. 5.8%) and less likely HR+/HER2- (50.0% vs. 73.6%) and TNBC (13.5% vs. 20.7%), compared to non-HER2E (p &amp;lt; 0.001). No significant differences in grade, TILs, Ki67 and histotype were observed. Overall, 140/776 genes were significantly downregulated in HER2E vs. non-HER2E tumors, including genes related to cell adhesion, migration, DNA damage repair, apoptosis, estrogen signalling pathway, senescence. Conversely, 178/776 genes were significantly upregulated, including the tyrosine-kinase receptor FGFR4, genes involved in nuclear activity, DNA transcription regulation, MAP-kinase signaling pathways, proliferation, cytokine response, epithelial-to-mesenchymal transition (EMT), cell cycle progression, and immune-related genes such as CD274 (PD-L1 gene). DISCUSSION: A switch towards more aggressive IS from primary to advanced disease was observed, with an increase in HER2E prevalence. HER2E tumors, which tend to maintain their IS at the metastatic disease, showed upregulation of genes related to proliferation, survival and EMT, coherently with their well-known worse prognosis. FGFR4 and CD274 upregulation, along with downregulation of genes involved in DNA damage repair suggest these tumors might benefit from targeted therapeutic approaches. Genomic higher risk was not convoyed by consistent clinicopathological features, except for lower PR levels and HER2 overexpression at IHC. Further characterization according to primary/metastatic and HR status is ongoing. Intrinsic subtype distribution across primary and metastatic breast tumors Citation Format: Francisco Javier Muñoz-Carrillo, Laia Paré, Benedetta Conte, Adela Rodríguez, Patricia Galván, Esther Sanfeliu, Blanca González-Farré, Claudette Falato, Isabel Garcia-Fructuoso, Barbara Adamo, Nuria Chic, Olga Martínez-Sáez, Tomás Pascual, Reinaldo Moreno, Montserrat Muñoz, Fara Brasó-Maristany, Aleix Prat, Francesco Schettini, Maria Vidal. Clinico-Pathological and Molecular Characterization of HER2-Enriched Breast Tumors Independently of HER2 Status [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P2-23-16.

Prevalence of CKD of Unknown Etiology and its Potential Risk Factors in a Rural Population in Sri Lanka

Chronic kidney disease of unknown etiology (CKDu) is an emerging form of CKD that predominantly affects working-age adults belonging to agricultural communities living in discrete geographic areas. Disease hotspots have been identified in several countries, including El Salvador, Nicaragua, Guatemala, Mexico, India, Egypt, and Sri Lanka.1 Despite its widespread distribution, the main clinicopathological features of the disease are similar among the different communities.2

Practical Approach to Histological Diagnosis of Peripheral Nerve Sheath Tumors: An Update.

Peripheral nerve sheath tumors encompass a wide spectrum of lesions with different biological behavior, including both benign and malignant neoplasms as well as the recent diagnostic category, i.e., “atypical neurofibromatous neoplasm with uncertain biologic potential” to be used only for NF1 patients. Neurofibromas and schwannomas are benign Schwann-cell-derived peripheral nerve sheath tumors arising as isolated lesions or within the context of classical neurofibromatosis or schwannomatoses. Multiple tumors are a hallmark of neurofibromatosis type 1(NF1) and related forms, NF2-related-schwannomatosis (formerly NF2) or SMARCB1/LZTR1-related schwannomatoses. Perineuriomas are benign, mostly sporadic, peripheral nerve sheath tumors that show morphological, immunohistochemical, and ultrastructural features reminiscent of perineurial differentiation. Hybrid tumors exist, with the most common lesions represented by a variable mixture of neurofibromas, schwannomas, and perineuriomas. Conversely, malignant peripheral nerve sheath tumors are soft tissue sarcomas that may arise from a peripheral nerve or a pre-existing neurofibroma, and in about 50% of cases, these tumors are associated with NF1. The present review emphasizes the main clinicopathologic features of each pathological entity, focusing on the diagnostic clues and unusual morphological variants.

Non-infectious granulomatous disorders of the upper lip: clinicopathological analysis of 11 patients

BackgroundNon-infectious granulomatous disorders of the upper lip represent a special chapter of oral and maxillofacial pathology. In this work we report a case-series of this process, to analyse its main clinicopathological features and find differential data that allow us improve its diagnosis and understand its pathogenesis.MethodsWe present 11 cases of non-infectious granulomatous disorders of the upper lip, 8 women and 3 men with an age range of 29–84 years, who have been attended at the Oral Medicine Department of the IUCT (France) and the Oral Medicine Unit of the UPV/EHU (Spain). All clinicopathological data were collected in a specific protocol.ResultsWe recognized 4 different subtypes of non-infectious granulomatous disorders of the upper lip: (1) associated with Crohn’s disease (1 case), (2) associated with foreign body (2 cases), (3) associated with gingivitis lichenoid-like (4 cases), (4) idiopathic (4 cases).ConclusionsClinicopathological differences were identified between these subtypes. A good differential diagnosis is necessary in all cases to rule out the presence of local or systemic etiopathogenic factors.

Effect of peri-operative blood transfusions on long-term prognosis of patients with colorectal cancer.

Patients with colorectal cancer often present with anaemia and require red blood cell transfusions (RBCT) during their peri-operative course. Evidence suggests a significant association between RBCT and poor long-term outcomes in surgical patients, but the findings in colorectal cancer are contradictory. The aim of this retrospective, single-centre, cohort study was to investigate the prognostic role of peri-operative RBCT in a large cohort of patients with stage I-III colorectal cancer submitted to curative surgery between 2005 and 2017. The propensity score matching technique was applied to adjust for potential confounding factors. Among 1,414 patients operated within the study period, 895 fulfilled the inclusion criteria: 29.6% (n=265) received peri-operative RBCT. The group that received peri-operative RBCT was significantly older (p<0.001), had more comorbidities (p<0.001), more advanced tumours (p<0.001) and more colon tumours (p=0.002) and stayed in hospital longer (p<0.001). Post-operative mortality was 7-fold higher (2.3 vs 0.3%, p=0.01) in this group. Survival outcomes were significantly worse in the group receiving RBCT than in the group not receiving RBCT for both overall (64.5 vs 80.1%, p<0.001) and cancer-specific survival (74.3 vs 85.1%, p<0.001). On multivariable analysis, peri-operative RBCT was significantly associated with poorer overall survival (hazard ratio 1.51, p=0.009). When transfused and non-transfused cases were paired through the propensity score matching technique considering main clinico-pathological features, no differences in overall and cancer-specific survival were found. Our data suggest that, after adjustment for potential confounding factors, no significant association exists between RBCT and prognosis in colorectal cancer.

Practical Approach to the Diagnosis of the Vulvo-Vaginal Stromal Tumors: An Overview.

Background: The category of the “stromal tumors of the lower female genital tract” encompasses a wide spectrum of lesions with variable heterogeneity, which can be nosologically classified on the basis of their morphologic and immunohistochemical profiles as deep (aggressive) angiomyxoma (DAM), cellular angiofibroma (CAF), angiomyofibroblastoma (AMFB) or myofibroblastoma (MFB). Despite the differential diagnosis between these entities being usually straightforward, their increasingly recognized unusual morphological variants, along with the overlapping morphological and immunohistochemical features among these tumours, may raise serious differential diagnostic problems. Methods and Results: The data presented in the present paper have been retrieved from the entire published literature on the PubMed website about DAM, CAF, AFMB and MFB from 1984 to 2021. The selected articles are mainly represented by small-series, and, more rarely, single-case reports with unusual clinicopathologic features. The present review focuses on the diagnostic clues of the stromal tumours of the lower female genital tract to achieve a correct classification. The main clinicopathologic features of each single entity, emphasizing their differential diagnostic clues, are discussed and summarized in tables. Representative illustrations, including the unusual morphological variants, of each single tumour are also provided. Conclusion: Awareness by pathologists of the wide morphological and immunohistochemical spectrum exhibited by these tumours is crucial to achieve correct diagnoses and to avoid confusion with reactive conditions or other benign or malignant entities.

Associations between the Levels of Estradiol-, Progesterone-, and Testosterone-Sensitive MiRNAs and Main Clinicopathologic Features of Breast Cancer.

Despite the existing advances in the diagnosis and treatment of breast cancer (BC), the search for markers associated with the clinicopathological features of BC is still in demand. MiRNAs (miRs) have potential as markers, since a change in the miRNA expression profile accompanies the initiation and progression of malignant diseases. The receptors for estrogen, androgen, and progesterone (ER, AR, and PR) play an important role in breast carcinogenesis. Therefore, to search for miRNAs that may function as markers in BC, using bioinformatic analysis and the literature data, we selected 13 miRNAs whose promoter regions contain binding sites for ER or AR, or putative binding sites for ER, AR, and PR. We quantified their expression in MCF-7 cells treated with estradiol, progesterone, or testosterone. The levels of miRNAs sensitive to one or more of these hormones were quantified in BC samples (n = 196). We discovered that high expression levels of miR-190b in breast tumor tissue indicate a positive ER status, and miR-423 and miR-200b levels differ between patients with and without HER2 amplification. The miR-193b, -423, -190a, -324, and -200b levels were associated with tumor size or lymph node status in BC patients, but the presence of these associations depended on the status and expression level of ER, PR, HER2, and Ki-67. We also found that miR-21 expression depends on HER2 expression in ER- and/or PR-positive BC. The levels of miRNA were significantly different between HER2 0 and HER2 1+ tumors (p = 0.027), and between HER2 0 and HER2 2+, 3+ tumors (p = 0.005).

Significance of p53, p27, Ki-67, E-cadherin, and HER2 expression in upper urinary tract urothelial carcinoma

BackgroundThe study investigated the expression and the clinicopathological significance of p53, p27, Ki-67, E-cadherin, and HER2 in upper urinary tract urothelial carcinomas (UTUC) from Tunisian patients. We performed a retrospective study of 66 UTUC. Main clinicopathological features were reported. The expression of p53, p27, Ki-67, E-cadherin, and HER2 was investigated by immunohistochemistry on whole tissue section.ResultsExpression of p53, Ki-67, p27, E-cadherin, and HERE2 was reported in 36.4%, 69.7%, 90.9%, 100%, and 0% of cases, respectively. p53 expression was associated with stage (p = 0.001), positive surgical margin (p = 0.005), and shorter recurrence-free survival (RFS; Log Rank test, p = 0.026). Ki-67 and p27 expression was associated with stage (p < 0.001 and p = 0.001, respectively) and grade (p < 0.001 and p = 0.001, respectively). Using Kaplan-Meier test, the positive surgical margin was associated with shorter RFS compared to free surgical margin (Log Rank test, p = 0.031). Moreover, in univariate Cox regression analysis, surgical margin (p = 0.041; HR 0.325, 95% CI 0.110–0.956) and p53 expression (p = 0.035; HR 0.328, 95% CI 0.116–0.925) were the significant factors associated with RFS.ConclusionsTogether, our findings suggest that positive surgical margin and p53 expression were potential prognostic factors of UTUC since both were associated with shorter RFS in Tunisian patients.

What is new in epithelioid soft tissue tumors?

Epithelioid cell features mimicking carcinomas characterize a variety of histogenetically, phenotypically, and molecularly distinct subsets of mesenchymal neoplasms. In a pathogenetic sense, epithelioid soft tissue tumors basically fall into three main genetic categories: (1) switch/sucrose non-fermenting (SWI/SNF) complex-deficient tumors (with epithelioid sarcoma as their prototype); (2) epithelioid neoplasms driven by specific rare gene fusions (such as sclerosing epithelioid fibrosarcoma with EWSR1 fusions and GLI1-related malignant epithelioid soft tissue neoplasms); and (3) a heterogeneous group encompassing epithelioid variants of diverse other entities. Notably, lesions in the first and third groups may display variable, occasionally prominent, rhabdoid cell morphology, thus further complicating their differential diagnosis. This review summarizes the main clinicopathological, phenotypic, and genotypic features of these diseases and discusses their pertinent differential diagnostic considerations.

Extranodal NK/T-cell lymphoma in Tunisia: clinicopathological features, immunophenotype and EBV infection

BackgroundExtranodal NK/T-cell lymphomas (ENKTL) are rare non-Hodgkin’s lymphomas with aggressive clinical behavior. ENKTL are frequently associated with the Epstein-Barr virus (EBV). Data on ENKTL in Africa and Arab world are extremely limited. The study investigated the clinicopathological characteristics, EBV infection, and immunophenotype of ENKTL in Tunisia. We conducted a retrospective study of ENKTL. Main clinicopathological features were reported. The expression of CD3, CD4, CD5, CD8, CD20, CD56, CD57, and Granzyme B were analyzed by immunohistochemistry. EBV infection was detected by IHC (LMP-1) and Epstein-Barr encoding region (EBER1/2) in situ hybridization.ResultsA total of nine ENKTL were identified (mean age of 48 years and male-to-female ratio of 8:1). There were five nasal ENKTL, and the remaining four cases had extranasal involvement (palate, sub-mandibular gland, skin, and soft tissues of the ankle). The histopathology showed a lymphoid and pleomorphic proliferation characterized by images of angiocentrism. Strong and diffuse CD3 expression was observed in all cases. Tumor cells exhibited an expression of CD5 (two cases), CD8 (three cases), CD56 (six cases), CD57 (three cases), and Granzyme B (eight cases). All ENKTL cases were EBV-associated. Overall 5-year survival rate was 57%. Although six ENKTL were diagnosed at early clinical stages, the prognosis was unfavorable and associated with patient death in three cases.ConclusionsENKTL are exceptional in Tunisia with unfavorable outcome. Histopathological diagnosis remains challenging in clinical practice. However, a careful histopathological examination combined with a correct interpretation of immunohistochemistry and in situ hybridization results refines the ENKTL diagnosis.

HER2 Positivity Predicts Unresponsiveness to EGFR-Targeted Treatment in Metastatic Colorectal Cancer.

HER2 amplification is detected in 3% of patients with colorectal cancer (CRC), making tumors in the metastatic setting vulnerable to double pharmacological HER2 blockade. Preclinical findings show that it also might impair response to anti-epidermal growth factor receptor (EGFR) treatment. Patients with KRAS exon 2 wild-type metastatic CRC underwent molecular screening of HER2 positivity by HERACLES criteria (immunohistochemistry 3+ or 2+ in ≥50% of cells, confirmed by fluorescence in situ hybridization). A sample of consecutive HER2-negative patients was selected as control. A regression modeling strategy was applied to identify predictors explaining the bulk of HER2 positivity and the association with response to previous anti-EGFR treatment. From August 2012 to April 2018, a total of 100 HER2-positive metastatic CRC tumors were detected out of 1,485 KRAS exon 2 wild-type screened patients (6.7%). HER2-positive patients show more frequently lung metastases (odds ratio [OR], 2.04; 95% confidence interval [CI], 1.15-3.61; p = .014) and higher tumor burden (OR, 1.48; 95% CI, 1.10-2.01; p = .011), and tumors were more likely to be left sided (OR, 0.50; 95% CI, 0.22-1.11; p = .088). HER2-positive patients who received treatment with anti-EGFR agents (n = 79) showed poorer outcome (objective response rate, 31.2% vs. 46.9%, p = .031; progression-free survival, 5.7 months vs. 7 months, p = .087). Testing for HER2 should be offered to all patients with metastatic CRC because the occurrence of this biomarker is unlikely to be predicted based on main clinicopathological features. Patients with HER2-amplified metastatic CRC are less likely to respond to anti-EGFR therapy. Patients with HER2-amplified/overexpressed metastatic colorectal cancer (mCRC) harbor a driver actionable molecular alteration that has been shown in preclinical models to hamper efficacy of the anti-epidermal growth factor receptor (EGFR) targeted therapies. The present study confirmed that this molecular feature was associated with worse objective tumor response and shorter progression-free survival in response to previous anti-EGFR therapies. Moreover, it was found that the occurrence of this biomarker is unlikely to be predicted based on main clinicopathological features. Therefore, HER2 status assessment should be included in the molecular diagnostic workup of all mCRC for speedy referral to clinical trials encompassing HER2-targeted double blockade independently of previous anti-EGFR treatment.

Abstract P4-10-10: Assessment of short inter-pregnancy interval in breast cancer diagnosed during pregnancy

Abstract Background: The relationship between pregnancy and breast cancer (BC) risk is not fully understood. Most of the literature has described this interaction in terms of the age at first pregnancy and the number of full-term pregnancies. During the prospective accrual of the “Joven &amp; Fuerte” young women with BC program in Mexico, we identified patients with pregnancy-associated BC (PABC) that experienced a short inter-pregnancy interval (SIPI) (&amp;lt;18 months between a live birth and the beginning of a following pregnancy). To our knowledge, there are no descriptions of the interaction between SIPI and PABC. Objective: We aim to assess the occurrence of SIPI in patients with PABC, as well as describe their clinical features at presentation. Results: We included patients accrued in the “Joven &amp; Fuerte” program from August 2014 and June 2018 at three Mexican cancer centers. A total of 375 patients ≤40 years-old with newly-diagnosed BC were assessed. 37 patients were diagnosed with PABC (10%), 21 during pregnancy and 16 after pregnancy. 6/37 (16%) patients with PABC experienced a SIPI, all diagnosed during pregnancy (28% of 21). The main clinicopathological features are described in the table 1. Table 1.Clinicopathological features of patients with PABC and SIPICaseAge at BC diagnosis (years)IPI (months)Pregnancy trimester at diagnosisStageBC subtype131183rdIIBNot available23262ndIIIAHR neg, HER2 pos337143rdIIAHR neg, HER2 pos436152ndIVHR pos, HER2 neg53142ndIIIAHR pos, HER2 neg63142ndIIICNot available Conclusion: According to the phenomena seen in this cohort of young BC patients, we hypothesize that SIPI may increase the incidence and/or modify the clinical outcomes of PABC. The evidence from clinical and laboratory data suggest that the mechanisms that could alter the interaction include, but are not limited to, the prolongation of the exposure to high concentrations of estrogens or their genotoxic metabolites, interaction with the effect of progesterone and other pregnancy-associated hormones on breast tissue, and immunologic factors. To date, to our knowledge there is no evidence about the effect of SIPI in PABC. Thus, research in this area should be encouraged, particularly in vulnerable women in limited-resource settings, where SIPI is, unfortunately, a common occurrence, and might represent a risk factor for BC/PABC. Citation Format: Diaz-Perez H, Del Toro-Mijares R, Lopez-Martinez EA, Muñoz-Lozano JF, Fonseca A, Platas A, Martinez-Cannon BA, Barragan-Carrillo R, Castro-Carrasco J, Limon-Gomez S, Villarreal-Garza C. Assessment of short inter-pregnancy interval in breast cancer diagnosed during pregnancy [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P4-10-10.

Aberrant DNA methylation is associated with aggressive clinicopathological features and poor survival in cutaneous melanoma.

Promoter methylation of tumour suppressor genes (TSGs) has recently been implicated in the pathogenesis of several types of cancer. Regarding melanoma, over 100 genes that contribute to its pathogenesis have been identified to be aberrantly hypermethylated. This is a retrospective observational study that aims to analyse the prevalence of CpG island methylation in a series of primary melanomas, to identify the associations with the main clinicopathological features, and to explore the prognostic significance of methylation in melanoma survival. DNA methylation was analysed using methylation-specific multiplex ligation-dependent probe amplification in a series of 170 melanoma formalin-fixed paraffin-embedded tumour samples. The relationship between the methylation status, known somatic mutations and clinicopathological features was evaluated. Disease-free survival (DFS) and overall survival (OS) were displayed by the Kaplan-Meier method. In the entire cohort, one or more genes were detected to be methylated in 55% of the patients. The most prevalent methylated genes were RARB 31%, PTEN 24%, APC 16%, CDH13 16%, ESR1 14%, CDKN2A 6% and RASSF1 5%. An association between aberrant methylation and aggressive clinicopathological features was observed (older age, increased Breslow thickness, presence of mitosis and ulceration, fast-growing melanomas, advancing stage and TERT mutations). Furthermore, Kaplan-Meier survival analysis showed a correlation of methylation and poorer DFS and OS. Aberrant methylation of TSGs is a frequent event in melanoma. It is associated with aggressive clinicopathological features and poorer survival. Epigenetic alterations may represent a significant prognostic marker with utility in routine practice.

HPV infection and p16INK4A and TP53 expression in rare cancers of the uterine cervix

Cervix cancer remains among most commonly diagnosed cancer in developing countries. Except squamous cell carcinoma and adenocarcinoma, the etiopathology and oncogenic mechanisms of rare cancers remain largely unknown. The study was performed to investigate the value of HPV infection and the expression of p16INK4A and TP53 in rare primitive cancers of the cervix.We conducted a retrospective study of rare primitive cancers of the cervix. Main clinicopathological features were reported. HPV infection was detected by in situ hybridization. Expression of p16INK4A and TP53 was analyzed by immunohistochemistry.Overall, seven cases were identified, including basaloid squamous cell carcinoma (BSCC, n = 2), small cell neuroendocrine carcinoma (SCNEC), granulocytic sarcoma without acute myeloid leukemia, leiomyosarcoma, primitive neuroectodermal tumor and botryoid-type embryonic rhabdomyosarcoma. The mean age of patients was 53.7 years. Four cancers were diagnosed at advanced stages. The prognosis was unfavorable and associated with patient death in five cases. HPV types 16/18 were detected in BSCCs and SCNEC. Strong and diffuse p16INK4A overexpression was described in the nucleus and the cytoplasm of all tumor cells of BSCCs and SCNEC. The remaining cancers exhibited only scattered and focal p16INK4A staining. Mutated TP53 protein was detected in BSCC (case 1) and GS.Rare cancers of the cervix are aggressive and associated with poor prognosis. In contrast to mesenchymal tumors, BSCCs and SCNEC are etiologically related to high-risk HPV infection and could be identified by block positive p16INK4A overexpression as common cancers of the cervix. TP53 mutations are not a negligible genetic event in rare cervical cancers.

Clinicopathological characteristics and HER2 status in metastatic colorectal cancer patients: Results of a diagnostic model development study.

581 Background: We have reported with the HERACLES Trial that HER2 amplification is a clinically relevant genetic alteration in metastatic colorectal cancer (mCRC). With present study, we aim to develop and internally validate a new diagnostic model for HER2 status in patients with mCRC based on clinicopathological characteristics to improve selection for HER2-targeted therapies and to refine negative selection for EGFR-targeted agents. Methods: Patients with KRAS exon 2 WT mCRC underwent molecular screening of HER2 according to HERACLES criteria (immunohistochemistry 3+ or 2+ in equal or more than 50% of cells, confirmed by FISH) for enrollment in HERACLES clinical trials with HER2-targeted therapies. All HER2-positive cases and a fraction of negative consecutive cases were annotated with clinical and pathological variables. A multivariable logistic regression model with a linear combination of all clinical and pathological characteristics as predictors was fitted to the complete set of data. A regression modeling strategy was applied to the full model to identify predictors explaining the bulk of HER2 amplification. Results: From August 2012 to June 2017, a total of 80 HER2-positive mCRC cases were detected out of 1355 screened patients. The large majority of HER2-positive primary tumors appeared to be left colon- or rectal-sided (88.0%). None of the relevant clinicopathological features explained the bulk of HER2 amplification, even though trends were observed for sidedness (left colon and rectal &gt; proximal, OR 1.75, 95% CI 0.76-4.16), tumour grading (high &gt; low, OR 2.21, 95% CI 0.19-26.38), and metastatic burden (high &gt; low, OR 1.29, 95% IC 0.94-1.77). In a secondary analysis, patients with HER2-amplified mCRC who received treatment with anti-EGFR agents (n = 64) showed poorer outcome (objective response rate: 30% vs 55%, p = 0.044 and progression-free survival: 5.8 months vs 7 months, p = 0.056). Conclusions: Testing for HER2 should be offered to all patients with mCRC since it is unlikely to predict the occurrence of this biomarker based on main clinicopathological features. Patients with HER2-amplified mCRC are less likely to respond to anti-EGFR therapy.