Precision oncology relies on precision diagnostics, and histopathological diagnosis, along with biomarker evaluation, currently represents the cornerstone for personalized treatment. In gastrointestinal neoplasms, diagnostic assessment and molecular profiling are often performed on biopsy tissue, which may be quantitatively/qualitatively limited. Therefore, appropriate sample management is essential to avoid unnecessary waste and to obtain all the information necessary for treatment planning. Several factors may significantly impact biomarker testing: (i) pre-analytical issues; (ii) heterogeneity in biomarker expression; (iii) lack of standardization in biomarker testing and evaluation. Moreover, in the metastatic setting, inadequate/incomplete clinical information can lead to inappropriate sample handling, with negative implications. The application of appropriate guidelines in testing and reporting biomarker status according to clinical context is, therefore, strongly encouraged. In this position paper, the Italian Group of Gastrointestinal Pathologists (GIPAD), a section of the Italian Society of Pathological Anatomy and Cytology (SIAPeC-IAP), aims to summarize all the clinical and pathological requirements for adequate assessment of prognostic and predictive biomarkers in the gastrointestinal oncology patient, from biopsy acquisition to diagnostic reporting.

Background: Colorectal adenocarcinoma remains one of the leading causes of cancer-related mortality worldwide despite substantial advances in diagnosis and treatment. Resistance to apoptosis is a hallmark of tumor progression and therapeutic failure. Inositol 1,4,5-trisphosphate receptor type 3 (IP3R3), a key mediator of endoplasmic reticulum-to-mitochondria Ca²⁺ transfer and intrinsic apoptosis, has been implicated in tumor biology, but its clinicopathological significance in colorectal adenocarcinoma remains poorly defined. This study investigated IP3R3 expression in human colorectal adenocarcinoma and evaluated its association with clinicopathological features. Methods: A prospective cohort of 179 patients with colorectal adenocarcinoma was enrolled. IP3R3 protein expression was assessed by Western blotting and immunohistochemistry in paired tumor and matched adjacent normal colonic tissues. The findings were independently validated using publicly available Clinical Proteomic Tumor Analysis Consortium (CPTAC) datasets. Results: IP3R3 expression was significantly reduced in colorectal adenocarcinoma compared with matched normal colonic mucosa. Loss of IP3R3 expression was independent of TNM stage and primary tumor location but was strongly associated with histological dedifferentiation, progressively declining from well- and moderately differentiated tumors to poorly differentiated lesions, in which IP3R3 expression was frequently undetectable. Immunohistochemical analysis confirmed progressive loss of IP3R3 during disruption of glandular architecture, while independent CPTAC proteomic datasets validated the observed expression pattern. Conclusions: Loss of IP3R3 expression is closely associated with histological dedifferentiation in colorectal adenocarcinoma, independently of TNM stage and primary tumor location. These findings identify IP3R3 as a candidate biomarker of tumor differentiation and suggest that reduced IP3R3 expression reflects impaired apoptotic competence and the biological state of colorectal tumors. Further studies are warranted to determine whether restoration of IP3R3-dependent ER-to-mitochondria Ca²⁺ signaling may improve therapeutic responsiveness in colorectal cancer.

Histologic evaluation of colonic biopsies in patients with chronic diarrhea or long-standing colitis is frequently performed in the setting of incomplete clinical, endoscopic, or laboratory information. In this context, overlapping morphologic features across different etiologies often lead to nonspecific or misleading diagnoses, such as “chronic colitis,” with potential implications for patient management.To improve diagnostic clarity and clinicopathologic communication, the Italian Group of Digestive Disease Pathology (GIPAD) developed a structured, pattern-based histologic approach for the interpretation and reporting of adult colitis with chronic architectural damage, based on multidisciplinary discussion and critical appraisal of the literature. Distinct histologic patterns are described and correlated with relevant differential diagnoses.Major patterns of colitis with chronic architectural damage are identified, and for each pattern, key morphologic features and principal differential diagnoses—including inflammatory bowel disease and other conditions such as drug-related injury, ischemia, infection, diversion colitis, and immune-mediated disorders—are discussed.A pattern-based histologic approach provides a practical framework for reporting colitis with chronic architectural damage. This strategy narrows differential diagnoses, avoids nonspecific terminology, and supports clinical decision-making, while preserving the primacy of integrated clinicopathologic diagnosis when sufficient information is available.

Bullous pemphigoid (BP) has increasingly been reported in patients with melanoma, particularly in association with modern oncological therapies. We describe a case of BP confined to the cutaneous field that harboured the primary melanoma and in-transit metastases following sequential immune checkpoint inhibition and BRAF/MEK-targeted therapy. This tumour-field-restricted pattern highlights a possible spatial link between melanoma biology, local immune dysregulation and BP pathogenesis.

Background: Several studies evaluated the role of variant allele frequency (VAF) as a clinical decision-making tool for targeted therapies. However, its predictive role for treatment response in epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer (NSCLC) remains debated. This study investigates the relationship between VAF and early tumor shrinkage (ETS) and deepness of response (DpR). We also explored the impact of previously undescribed compound uncommon EGFR mutations on osimertinib activity. Methods: We retrospectively analyzed data from patients with advanced EGFR-mutated NSCLC, treated with osimertinib. VAF was obtained through NGS. We calculated corrected VAF (cVAF) based on the percentage of tumor cells. ETS and DpR were assessed according to RECIST 1.1 criteria. Molecular modeling was performed to predict the impact of novel compound EGFR mutations on osimertinib binding and EGFR protein structure. Results: We included 16 patients, who met the eligibility criteria. We found no significant correlation between cVAF and ETS or DpR, suggesting that cVAF may not have a direct effect on early or late tumor response to osimertinib. Median cVAF was 14%. Median progression-free survival and overall survival were longer in patients with higher VAF, even though they were not statistically significant. We identified two previously unreported compound EGFR mutations: N771Y + L858R and L718V + K713R + L858R. Conclusions: This study demonstrates that cVAF of EGFR mutations is not significantly associated with ETS or DpR during osimertinib in mNSCLC patients. Survival does not appear to be influenced by cVAF either. The identification and structural characterization of novel compound EGFR uncommon mutations may explain the benefit experienced by patients.

PURPOSE:Pituitary adenomas (PAs) are generally benign tumors with varying clinical presentations. While functioning PAs (FPAs) secrete hormones leading to distinct endocrine disorders, non-functioning PAs (NFPAs) often manifest with mass effect symptoms. Current medical therapies for PAs have limited efficacy, particularly for NFPAs. This highlights the need for new diagnostic and therapeutic targets. This study aimed to investigate the expression of Neuro-Oncological Ventral Antigen 2 (NOVA2), a factor involved in alternative splicing, in normal pituitary glands and PAs, to evaluate its potential as a novel therapeutic target. METHODS:Tissue samples from 12 PA patients (9 NFPAs and 3 FPAs) and 8 normal pituitary glands were collected. Immunohistochemical analysis was performed to assess NOVA2 expression. Semi-quantitative evaluation of NOVA2 staining was conducted using Histoscore. RESULTS:NOVA2 was expressed in the endothelial cells of both PAs and normal pituitary glands, with higher expression in PAs. Notably, NOVA2 was present in PA cells regardless of adenoma type, while normal pituitary epithelial cells were negative for NOVA2 expression. There was no statistically significant difference in NOVA2 expression between FPAs and NFPAs. CONCLUSIONS:This is the first study to demonstrate that NOVA2 is expressed in PA cells but not in normal pituitary epithelial cells. These findings suggest that NOVA2 could serve as a potential target for diagnostic and therapeutic strategies in PAs, especially considering the lack of specific biomarkers and effective medical therapies for these tumors. Further research with a larger sample size is warranted to validate these preliminary findings.

A subset of gastric cancers (GCs) is linked to Epstein-Barr virus (EBV) infection. This study aims to characterize the histopathological and molecular features of EBV-associated GCs (EBVaGCs), focusing on predictive biomarkers and genomic and transcriptomic analysis. A total of 35 primary EBVaGCs were considered. The presence of EBV was confirmed with in situ hybridization. Immunohistochemical analyses for HER2, PD-L1, claudin 18.2, and mismatch repair proteins were performed. Genomic and transcriptomic profiles were assessed using AmoyDx Master Panel, which can identify single-nucleotide variants, InDels, and copy number variations on 571 hot genes, as well as microsatellite status, tumor molecular burden, and homologous recombination deficiency at the DNA level; however, at the RNA level, it identifies rearrangements/fusions in 45 genes and also quantifies the expression of 2396 cancer-related transcripts. The following histotypes were identified: carcinoma with lymphoid stroma (CLS; 69%), tubular (20%), and mixed (11%). Most cases were associated with atrophic gastritis (71%), and only 11% with dysplasia. The vast majority (94%) of EBVaGCs expressed EBV-encoded RNA in all tumor cells. Mismatch repair deficiency and HER2 overexpression were each observed in 6% of cases, whereas all tumors had a PD-L1-combined positive score ≥10. Sixty-six percent of cases showed moderate/strong claudin 18.2 expression in ≥75% of cancer cells. The most frequently altered genes were PIK3CA (41%) and ARID1A (17%). Transcriptomic analysis revealed substantial differential gene expression between EBVaGCs and EBV-negative controls, with upregulation of genes involved in antigen presentation, natural killer cell-mediated cytotoxicity, and cytokine-cytokine receptor interaction in EBVaGCs. Within EBVaGC, CLS showed higher expression of immune-related transcripts and higher PD-L1 expression than other histotypes. This study establishes EBVaGC as a distinct molecular class, with a distinctive profile of genomic alterations and expression of predictive biomarkers, and also with a unique immune microenvironment with enhanced cytotoxic activity. The findings highlight EBV’s role in early tumor development and EBVaG-CLS as a distinct subgroup within EBVaGC, characterized by unique morphologic features and a pronounced immune activation profile.

Triple-negative breast cancer (TNBC) is a particularly aggressive and metastatic subtype, characterized by the absence of estrogen, progesterone, and human epidermal growth factor 2 receptors. Outcomes for TNBC patients vary widely, suggesting this classification encompasses different cancers with distinct histological, genomic, and immunological profiles, leading to variable prognoses. The tumor microenvironment, particularly the expression and localization of promyelocytic leukemia protein (PML) in tumor-associated macrophages (TAMs), can influence patient outcomes by modulating inflammation. The beneficial prognostic role of increased tumor-infiltrating lymphocytes (TILs) in TNBC is well-established. In this retrospective study, we found that PML expression in tumor cells is inversely related to the presence of TILs and is associated with poorer outcomes. Patients with disease recurrence exhibited higher levels of TAMs with predominantly nuclear-localized PML, in contrast to patients who showed complete recovery. The accumulation of PML in the nucleus reduces its presence at ER-mitochondria contact sites, impairing its interaction with the NLRP3 inflammasome and leading to increased IL-1β secretion. This promotes a pro-inflammatory tumor microenvironment as seen in patients with adverse outcomes. Our findings suggest that both PML expression in cancer cells and its localization in TAMs can serve as additional prognostic factors, highlighting the potential of PML as a therapeutic target in TNBC.

PURPOSE:This bi-centric pilot study investigates the predictive value of pre-treatment [18F]FDG PET/CT radiomics for assessing therapy response in primary mediastinal B-cell lymphoma (PMBCL). METHODS:All PMBCL patients underwent PET/CT with [18F]FDG between January 2011 and January 2022 at Policlinico Tor Vergata University Hospital of Rome (70% training and 30% internal validation cohort) and Sant'Anna University Hospital of Ferrara (external validation cohort). The Deauville score (DS) was used as a predictor of therapy response (DS1-DS3 vs. DS4/DS5). A total of 121 quantitative radiomics features (RFts) were extracted from manually segmented volumes of interest (VOIs) in PET and CT images, according to IBSI. ComBat harmonization was applied to correct the center variability of features, followed by class balancing with SMOTE. Two machine learning (ML) prediction models, the PET model and the CT model, were independently developed using robust RFts. For each ML model, two different algorithms were trained (i.e., Random Forest, RF, and Support Vector Machine, SVM) using 10-fold cross validation, tested on the internal/external validation set. Receiver operating characteristic (ROC) curves, area under the curve (AUC), classification accuracy (CA), precision (Prec), sensitivity (Sen), specificity (Spec), true positive (TP) scores, and true negative (TN) scores were computed. RESULTS:The entire dataset was composed of 29 samples for the Rome cohort (23 from D1-D3 and 6 from D4/D5) and 9 samples for the Ferrara cohort (4 from D1-D3 and 5 from D4/D5). A total of 27 RFts were identified as robust for each imaging modality. Both the CT and PET models effectively predicted the Deauville score. The performance metrics of the best classifier (SVM) for the CT and PET models in external validation were AUC = 0.75/0.80, CA = 0.85/0.77, Prec = 0.97/0.67, Sen = 0.60/0.80, Spec = 0.98/0.75, TP = 75.0%/66.7%, and TN = 77.8%/85.7%, respectively. CONCLUSIONS:ML models trained on [18F]FDG PET/CT radiomic features in PMBLC patients could predict the Deauville score.

Introduction: Colorectal cancer (CRC) is the third most frequent malignancy and the second cause of cancer-related death worldwide. CRC is characterized by morphologic and biological heterogeneity, and molecular profiling is required to select appropriate treatment in the metastatic setting. Mutations in KRAS are detected in approximately 40% of CRCs, with prognostic and predictive value, and with the most frequent being p.G12D. Nonetheless, there are few data on the morphologic features in KRAS-mutated CRCs. Materials and Methods: We retrospectively collected clinicopathological features and molecular profiles of CRCs in a multicenter cohort. Results: A total of 2816 patients from 12 centers were included. KRAS mutation was found in 47.4% of cases; Gly12Asp was detected in 23.9%, with different mutation frequencies between centers. Clinicohistological features associated with Gly12Asp mutation included younger patient age (≤70 years of age), higher prevalence in males (58.6%), NOS histotype (87.1%), low pathologic grade (73.9%), high grade budding—Bd3 (43.8%), and tumoral lympho-vascular invasion (68.9%). Conclusions: Recent data have pinpointed the prognostic and predictive value of Gly12Asp mutation, and our results contribute to understanding its biology, with particular focus on peculiar clinicopathological features. Moreover, we found significant differences in pathology reports and assays for molecular profiling in different centers, which can affect a standardized therapeutic approach in CRC.

BACKGROUND: Renal cell carcinoma (RCC), the most common solid tumor of the kidney, accounts for approximately 3% of all malignancies and has a higher incidence in Western countries. The current frontline treatment for metastatic RCC (mRCC) relies on immune checkpoint inhibitors (ICIs), alone or in combination with tyrosine kinase inhibitors (TKIs). Although initially effective, these therapies often lose efficacy due to the emergence of drug resistance, which severely limits long-term patient survival. Among the mechanisms exploited by cancer cells to evade treatment, autophagy has emerged as a key contributor. Here, we explore the role of autophagy in driving therapeutic resistance in kidney cancer. RESULTS: We demonstrate that metastatic RCC tissues display markedly higher levels of LC3 compared to matched primary tumors, suggesting a role of autophagy in disease progression. Pharmacological inhibition of autophagy with desmethylclomipramine (DCMI), a tricyclic antidepressant, significantly impairs RCC cell proliferation, invasion, and migration while promoting apoptosis. Notably, combining DCMI with the TKI Sunitinib enhances antitumor efficacy beyond either treatment alone, through a mechanism involving the p53/p21 pathway. CONCLUSION: Our findings underscore the importance of autophagy in the progression and therapeutic resistance of renal carcinoma. Targeting autophagy, particularly in combination with TKIs, may offer a promising strategy to overcome drug resistance and improve outcomes in patients with mRCC.

SARS-CoV-2 infection has been responsible of COrona VIrus Disease (COVID-19) pandemia and can cause a variety of symptoms including gastrointestinal disorders, abdominal pain and liver injury. The host receptor for SARS-CoV-2, ACE2, is expressed in gut and SARS-CoV-2 infection could induce vascular damage and immune system dysregulation, creating an inflammatory and hypercoagulable state, as widely described at the lung level. This work presents the case of a middle-aged Caucasian man admitted to the Hospital Emergency Department from the University Hospital of Ferrara (Italy), complaining of pain in the upper and middle region of the abdomen. The patient tested negative to the nose-oropharyngeal swab for SARS-CoV-2 four weeks after recovering from viral infection. The patient required resection of a segment of ileum and an ulcer of the bowel wall was recognized and sampled. Previous published results had confirmed the presence of the SARS-CoV-2 nucleocapsid protein, an increased human leukocyte antigen (HLA-G) and an altered morphology of microvilli in the ulcerated ileum of the patient when compared to the non-ulcerated ileum. The present study sought to deepen the consequences of SARS-CoV-2 infection. To this end, we evaluated the expression and co-expression of Vascular Endothelial Growth Factor (VEGF) and Fibronectin by immunohistochemical techniques. VEGF immunohistochemical expression was higher in the ulcer than in the control ileum sample and the non-ulcerated ileum areas and co-expressed with the SPIKE protein. Fibronectin staining was lower in control sample than in non-ulcerated and ulcerated ileum. Electron microscopy analysis showed alterations of the integrity of the intestinal barrier in the ulcerated area when compared to the non-ulcerated ileum or to the control sample. Although the patient was tested negative to nose-oropharyngeal swab for SARS-CoV-2, the SPIKE protein was detected in his terminal ileum, especially in the ulcerated areas. The presence of the viral protein was also associated with an increase of VEGF and Fibronectin. In addition to vascular changes, the SARS-CoV-2 infection altered the junctional apparatus among epithelial cells, making the tissue even more fragile and thus susceptible to the entry of pathogens and the development of further infections.

Background Triple-negative breast cancer (TNBC) stands out as a particularly aggressive and metastatic subtype, defined by its absence of estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2. It's important to note that outcomes for TNBC patients vary widely, suggesting this classification encompasses various cancers with different histological, genomic, and immunological profiles, leading to distinct prognoses. Our prior research revealed that the tumor microenvironment, especially the expression and localization of promyelocytic leukemia protein (PML) within tumor-associated macrophages (TAMs), can influence patient outcomes by affecting the inflammatory environment. The beneficial prognostic role of increased tumor-infiltrating lymphocytes (TILs) in TNBC is also well-established. Methods This is a retrospective cohort study composed of a total of 20 female patients affected by TNBCS, divided into two groups according to the observed outcome in a 10-year follow-up: 10 TNBC patients showing complete remission of the disease and 10 TNBC patients experiencing tumor recurrence and death within the follow-up. The collected histological tumor samples were stained to evaluate TILs and TAMs presence and PML expression. Results We found that PML expression in tumor cells is inversely related to the presence of TILs and is associated with worse patient outcomes. Furthermore, we discovered that patients with disease recurrence exhibited a higher number of TAMs with predominantly nuclear-localized PML, unlike what was observed in patients with complete disease recovery. This accumulation of PML in the nucleus reduces its presence at ER-mitochondria contact sites, thereby impairing its interaction with the NLRP3 inflammasome and leading to increased IL-1β secretion. This promotes a pro-inflammatory tumor microenvironment, as seen in patients with adverse outcomes. Conclusions Our findings suggest that both PML expression in cancer cells and its localization in TAMs can serve as additional prognostic factors, alongside TIL abundance, indicating the potential of PML as a target for TNBC therapy.

Objectives: To evaluate the in vitro effect of tofacitinib on autophagy activity of psoriatic arthritis (PsA) fibroblastlike synoviocytes (FLS), and to confirm its activity on infiammatory and invasive properties of FLS and synovial cells, deepening the impact on mitochondrial function.Methods: FLS, peripheral blood mononuclear cells (PBMCs), and synovial cells from active PsA patients were cultured with tofacitinib 1 mu M or vehicle control for 24 h. Autophagy was measured by Western blot and by fiuorescence microscopy. Chemokines/cytokines released into culture supernatants were quantified by ELISA, while invasive properties of FLS by migration assays. Specific mitochondrial probes were adopted to measure intracellular reactive oxygen species (ROS), mitochondrial potential, morphology, turnover and mitophagy. Oxygen consumption rate (OCR), refiecting oxidative phosphorylation, was quantified using the Seahorse technology. Differences were determined by adopting the non-parametric Wilcoxon signed rank test.Results: 18 patients with moderately-to-severely active PsA were enrolled. Tofacitinib significantly increased the levels of the autophagy markers LC3-II and ATG7 in PsA FLS compared to vehicle control, suggesting an increase in spontaneous autophagy activity; no effect was highlighted in PBMCs and synovial cells cultures. Tofacitinib reduced migration properties of PsA FLS, and reduced MCP-1 and IL-6 release into FLS and synovial cells cultures supernatants. Furthermore, tofacitinib decreased intracellular ROS production, increased basal OCR, ATP production and maximal respiratory capacity, and enhanced mitophagy and mitochondrial turnover.Conclusions: The JAK inhibitor tofacitinib reduces the pro-invasive and pro-infiammatory properties of PsA FLS. Autophagy induction and mitochondrial quality control modulation by tofacitinib might contribute to FLS function restoration.

BACKGROUND:The DNA mismatch repair (MMR) system is a highly preserved protein complex recognizing short insertions, short deletions, and single base mismatches during DNA replication and recombination. MMR protein status is identified using immunohistochemistry. Deficit in one or more MMR proteins, configuring deficient MMR status (dMMR), leads to frameshift mutations particularly clustered in microsatellite repeats. Thus, microsatellite instability (MSI) is the epiphenomenon of dMMR. In colorectal cancer (CRC), MMR/MSI status is a biomarker with prognostic and predictive value of resistance to 5-fluorouracil and response to immune checkpoint inhibitor therapy.SUMMARY:In this Review, we describe the challenges the practicing pathologist may face in relation to the assessment of MMR/MSI status and any open issues which still need to be addressed, focusing on pre-analytic issues, pitfalls in the interpretation, and technical aspects of the different assays.KEY MESSAGES:The current methods of detecting dMMR/MSI status have been optimized for CRCs, and whether these techniques can be applied to all tumor and specimen types is still not fully understood. Following the Food and Drug Administration (FDA), tissue/site agnostic drug approval of pembrolizumab for advanced/metastatic MSI tumors, MMR/MSI status in gastrointestinal tract is a common request from the oncologist. In this setting, several issues still need to be addressed, including criteria for sample adequacy.

Intrauterine transmission of SARS-CoV-2 (Severe Acute Respiratory Syndrome Corona Virus 2) is still matter of debate among scientists and there is limited information concerning this aspect of research. This could lead to severe complications of the growing fetus and, theoretically, of the newborn as well. We report the case of a male infant of 1,100 grams, born at 27th week of gestation to a SARS-CoV-2 mother, tested negative for viral detection at delivery. He was immediately admitted to neonatal Intensive Care Unit (ICU) for severe complications, where he died after 37 days by pulmonary embolism and thrombosis of the superior vena cava. After autopsy, SARS-CoV-2 N-protein and Spike RBD were detected in several tissues, particularly in the esophagus, stomach, spleen, and heart, with a significantly higher H-Score than the placenta. In conclusion, immunohistochemical analysis demonstrated SARS-CoV-2 NP and Spike RBD positivity in different tissues suggesting a possible intrauterine transmission. Newborn thrombo-embolism could be a complication of SARS-CoV-2 infection as observed in adult patients.

DearEditor, Biomarkers useful for the identification of patients at risk of developing vulvar squamous cell carcinoma (VSCC) on a vulvar lichen sclerosus (VLS) background could lead to relevant prognostic advantages. To date, the development of such biomarkers is an unmet medical need. Among potential biomarker molecules, microRNAs (miRNAs) have been gaining attention. Involvement of miRNAs in vulvar carcinogenesis has been addressed with some evidence.1–6 We aimed to investigate whether miRNA expression could be useful to predict the progression from VLS to VSCC. This study, which was approved by the University-Hospital of Ferrara institutional review board (identification code 452/2021/Oss/AOUFe), included two different groups of formalin-fixed paraffin-embedded (FFPE) histologically proven VLS specimens: (i) 10 VLS samples that did not evolve towards carcinoma from patients with a mean clinical follow-up of 6 years, defined as VLS free from cancer (VLSfc); (ii) 13 samples including either VLS in which an invasive VSCC was histologically diagnosed in a subsequent biopsy, obtained after the first histological diagnosis of lichen sclerosus (n = 2, LIC19 and LIC20), or 11 VLS samples in which an invasive VSCC was diagnosed in the same surgical specimen. Both these sample types were defined as VLS cancer-associated (VLSca).

<p>Supplementary Material and Methods, Results, 1 figure, and 1 table</p>

in this supplentary data file cases are reported

The aims of this systematic literature review (SLR) were to identify the effects of approved biological and targeted synthetic disease modifying antirheumatic drugs (b/tsDMARDs) on synovial membrane of psoriatic arthritis (PsA) patients, and to determine the existence of histological/molecular biomarkers of response to therapy. A search was conducted on MEDLINE, Embase, Scopus, and Cochrane Library (PROSPERO:CRD42022304986) to retrieve data on longitudinal change of biomarkers in paired synovial biopsies and in vitro studies. A meta-analysis was conducted by adopting the standardized mean difference (SMD) as a measure of the effect. Twenty-two studies were included (19 longitudinal, 3 in vitro). In longitudinal studies, TNF inhibitors were the most used drugs, while, for in vitro studies, JAK inhibitors or adalimumab/secukinumab were assessed. The main technique used was immunohistochemistry (longitudinal studies). The meta-analysis showed a significant reduction in both CD3+ lymphocytes (SMD -0.85 [95% CI -1.23; -0.47]) and CD68+ macrophages (sublining, sl) (SMD -0.74 [-1.16; -0.32]) in synovial biopsies from patients treated for 4-12 weeks with bDMARDs. Reduction in CD3+ mostly correlated with clinical response. Despite heterogeneity among the biomarkers evaluated, the reduction in CD3+/CD68+sl cells during the first 3 months of treatment with TNF inhibitors represents the most consistent variation reported in the literature.