Iranian Journal of Pathology

Abstract Antibiotic resistance has become a global challenge, particularly in hospitals, requiring special attention and precise measures. Adhering to proper guidelines for prescribing antibiotics and implementing antibiotic stewardship programs in hospitals can effectively prevent the rise of antibiotic resistance and reduce mortality caused by drug-resistant infections. In this regard, education, monitoring, and strict control over antibiotic prescriptions should be prioritized as key components in any healthcare setting.

Abstract Background & Objective: Nonalcoholic fatty liver disease, recently recognized as metabolic dysfunction-associated steatotic liver disease (MASLD), is a key factor in the development of chronic liver disease and the progression of liver fibrosis. It plays a significant role in increasing the risk of cirrhosis and hepatocellular carcinoma. Given the rapid developments in this field, keeping information up-to-date is essential to prevent misconceptions and ineffective decision-making. This study employs a scientometric approach to review scientific literature and analyze recent findings, offering a comprehensive overview of the current state of research in this field.
Methods: In this approach, we explored data related to publication metrics, public perceptions, scientific conference, mobile apps, AI tools, and new medications. This was done using a set of keywords, including "Non-alcoholic fatty liver disease," "Metabolic dysfunction-associated steatotic liver disease," "Mobile application," and "Artificial intelligence."
Results and Conclusion: This research highlights significant scientific advances in the field of MASLD, including major scientific meetings, highly cited publications, and the latest FDA-approved therapies. In addition, it examines emerging digital tools and public search frameworks, providing a structured picture of recent developments. These findings provide a comprehensive view of the dynamic MASLD research landscape and emphasize the roles of AI, mobile apps, and emerging therapies in its management.

Abstract Urinary tract infections (UTIs) caused by Trichosporon are a significant concern for hospitalized patients and those with weakened immune systems. This narrative review study aims to provide a comprehensive overview of UTIs caused by Trichosporon, including its frequency, risk factors, laboratory diagnostic aspects, drug resistance, and the importance of accurate identification in clinical settings. A search of international databases was conducted to identify relevant studies, and it was found that Trichosporon asahii, specifically the G1 type, is the predominant causative agent of UTIs among various Trichosporon species. Prolonged hospitalization and immunosuppressive drug use were identified as significant risk factors for this fungal infection. Conventional methods for laboratory identification are commonly used. Still, rapid and accurate tools such as Matrix-Assisted Laser Desorption-Ionisation-Time of Flight Mass Spectrometry (MALDI-TOF MS) and DNA sequencing can improve the diagnostic process. Against all T. asahii isolates for which this triazole, polyene, and echinocandin were tested, voriconazole demonstrated the most potent in vitro activity, while amphotericin B had high MIC values and echinocandins had inherent resistance. This review provides valuable insights into the clinical significance and management of UTIs caused by Trichosporon.

Abstract Background & Objective: The purpose of this research was to determine the frequency of algD, pslD, and pelF genes in biofilm formation among MDR and non-MDR clinical strains of Pseudomonas aeruginosa in Khorramabad, Iran (2024).
Methods: This cross-sectional study included all Pseudomonas aeruginosa isolates collected from various clinical samples in Khorramabad teaching hospitals in 2024. After confirming the isolates and determining their antibiotic resistance patterns using the disc diffusion method according to the Clinical and Laboratory Standards Institute (CLSI) guidelines, algD, pelF, and pslD genes were detected by PCR.
Results: The highest sensitivity was observed to imipenem (75%) and meropenem (71.3%), while the greatest resistance was recorded against ciprofloxacin, ceftazidime, and tobramycin 45 (56.25%). The frequencies of the algD, pelF, and pslD genes were 88.8, 76.3, and 96.3%, respectively. A significant association was found between the PelF and algD genes with multidrug resistance (MDR) (P<0.05).
Conclusion: The presence of multi-drug resistance (MDR) in this study indicates the need for serious measures to control infections caused by this bacterium. Further research is recommended to explore the contribution of biofilm-associated genes to the  development of multi-drug resistance (MDR).

Abstract Background & Objective: Triple-negative breast cancer (TNBC) is an aggressive subtype lacking estrogen, progesterone, and HER2 receptors, often leading to poor prognosis due to high recurrence and metastasis. FOXP3 expression, associated with suppressed anti-tumor immunity, is a potential prognostic marker in TNBC. However, the association between FOXP3 expression and disease-free survival (DFS) in TNBC remains controversial. This study aims to explore the relationship between FOXP3 expression and DFS in TNBC patients, contributing to the understanding of its prognostic significance.
Methods: This retrospective study included 47 TNBC patients. Immunohistochemistry examination assessed FOXP3 expression, which was then categorized into low and high expression based on an optimal cut-off point. Univariate and multivariate analyses were conducted using Cox regression test to determine association between variables and DFS. Survival analysis was assessed using the Kaplan-Meier method and the log-rank test.
Results: All patients were female mostly over 50 years old (66%). The majority had tumors >2 cm (87.2%) and LVI (66%). High-grade tumors (grade 3) were predominant (93.6%). Most patients showed moderate TIL levels (91.5%). No significant associations were found between FOXP3 expression and age (p=0.253), tumor size (p=0.308), lymph node status (p=0.466), tumor grade (p=0.476), LVI (p=0.422), patient's stage (p=0.644), and TILs (p=0.783). However, high FOXP3 expression was significantly associated with worse DFS (p=0.019). Additionally, a higher stage was associated with worse DFS (p=0.002).
Conclusion: High FOXP3 expression is associated with lower DFS in TNBC patients. FOXP3 expression was not associated with age, tumor size, lymph node status, tumor grade, LVI, TILs, or cancer stage.

Abstract Background & Objective: This study aimed to elucidate the complex interplay between insulin resistance (IR), type 2 diabetes mellitus (T2DM), and the expression of key inflammatory cytokines interleukin-6 (IL-6), interleukin-10 (IL-10), and interleukin-1 beta (IL-1β).
Methods: A cross-sectional study was conducted involving 100 participants categorized into four groups: IR only (n=30), T2DM without IR (DM-IR, n=20), T2DM with IR (DM+IR, n=20), and healthy controls (HC, n=30). mRNA levels of the cytokines in peripheral blood mononuclear cells (PBMCs) were quantified using qRT-PCR, and serum protein levels were assessed via ELISA.
Results: Significant upregulation of IL-6 mRNA in PBMCs was observed in the DM+IR and DM-IR groups compared to controls and the IR only group, while serum IL-6 protein was paradoxically lower in DM+IR compared to DM-IR. Both IL-10 mRNA and serum protein levels were elevated in the DM-IR group, suggesting a compensatory anti-inflammatory response, but were downregulated in the DM+IR group. IL-1β showed a similar pattern, with increased mRNA and serum protein in DM-IR and decreased serum protein in DM+IR.
Conclusion: The findings reveal distinct inflammatory cytokine profiles associated with IR and T2DM, highlighting discrepancies between mRNA and protein levels that suggest complex post-transcriptional and translational regulation. These results emphasize the necessity for careful interpretation of cytokine expression in the context of metabolic disorders.

Abstract Background & Objective: Accurate evaluation of the Ki-67 proliferation index is critical in the grading and prognostication of neuroendocrine neoplasms (NENs). This study aimed to compare three different methods of Ki-67 index assessment in primary gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs).
Methods: The Ki-67 proliferation index was assessed by immunohistochemical (IHC) staining in 41 cases of primary GEP-NENs. Two pathologists independently evaluated the Ki-67 index using two visual estimation methods: eyeballing and eye-counting under a light microscope. A third method involved manual counting of Ki-67–positive and –negative nuclei on a captured image using ImageJ software. Interobserver and intermethod reproducibility were analyzed using Pearson’s correlation coefficient (R) and the intraclass correlation coefficient (ICC) to assess agreement among the four observers and between each observer and the manual method.
Results: The ICC among the four observers was 0.993, indicating excellent interobserver agreement. The ICC between each observer’s score and the manual counting method was 0.994, also demonstrating high concordance.
Conclusion: All three methods, eyeballing, eye-counting, and manual counting using ImageJ, proved to be comparably effective in assessing the Ki-67 proliferation index in GEP-NENs. Notably, the simpler microscopic techniques of eyeballing and eye-counting showed excellent agreement with the manual image-based method, supporting their reliability in routine practice.

Abstract Background & Objective: Angiosarcomas (AS) are rare, aggressive malignant tumors characterized by marked histopathologic heterogeneity, often mimicking other neoplasms and complicating diagnosis. This 16-year retrospective study aimed to evaluate the clinicopathological spectrum of AS, with particular emphasis on diagnostic challenges and strategies for accurate identification.
Methods: We retrospectively reviewed 11 histologically confirmed cases of AS diagnosed at our institution between January 2008 and December 2023. The data collected included patient demographics, clinical presentation, tumor location, histopathologic features, immunohistochemical (IHC) profiles, treatment modalities, and clinical outcomes.
Results: Patient ages ranged from 25 to 62 years, with a slight female predominance (male-to-female ratio, 0.8:1). Tumor locations were variable, and histologic patterns ranged from well-differentiated, low-grade vascular proliferations resembling hemangiomas to poorly differentiated neoplasms mimicking pleomorphic undifferentiated sarcomas. IHC findings demonstrated overlapping marker expression, including cytokeratin (CK) positivity, which may lead to misdiagnosis as carcinoma, and loss of H3K27me3 expression, which can raise suspicion for malignant peripheral nerve sheath tumors (MPNST). Several cases also exhibited morphologic features closely resembling epithelioid hemangioendothelioma.
Conclusion: Angiosarcoma poses considerable diagnostic difficulty due to its morphologic variability and overlapping immunophenotypic profiles. Accurate diagnosis necessitates a multidisciplinary approach, integrating clinical, radiologic, and pathologic data. This study highlights the importance of diagnostic vigilance and comprehensive evaluation when assessing vascular neoplasms.

Abstract Background & Objective: Signal Transducer and Activator of Transcription 4 (STAT4) is a key transcription factor involved in immune signaling pathways and has been implicated in susceptibility to rheumatoid arthritis (RA) across various populations. However, its role in Iraqi Arab cohorts remains largely unexplored.
Methods: A case–control study was conducted including 68 RA patients and 39 age- and sex-matched apparently healthy individuals. The association between the STAT4 (rs7574865) polymorphism, serum STAT4 levels, RA susceptibility, and therapeutic response to methotrexate (MTX), MTX + infliximab, and tofacitinib was investigated using PCR–RFLP and ELISA techniques.
Results: The frequencies of the GT and (GT+TT) genotypes were significantly higher among RA patients than in controls under codominant and dominant models (P = .003 and P < .001, respectively). The T allele was also significantly more frequent in RA patients than in healthy individuals (P = .001). GT and TT genotypes were significantly associated with severe disease (P = .042) and poor response to tofacitinib compared with the GG genotype (P = .042). Serum STAT4 levels were markedly elevated in RA patients compared with controls (P = .01), particularly in those with severe RA (P = .042).
Conclusion: The STAT4 rs7574865 T allele may contribute to increased susceptibility to RA, greater disease severity, and reduced responsiveness to tofacitinib therapy in Iraqi patients.

Abstract Background & Objective: Neonatal cholestasis (NC) occurs in approximately 1 in 2500 live births. Autophagy-related gene 5 (ATG5) is a central component of the autophagy machinery, particularly in autophagosome formation. The autophagic process regulated by ATG5 has been implicated in various physiological and pathological conditions. This study aimed to evaluate the role of ATG5 in NC.
Methods: This retrospective study analyzed liver biopsies from 74 patients with NC. Immunohistochemical expression of ATG5 was assessed in hepatocytes and biliary epithelium.
Results: A significant association was observed between intrahepatic cholestasis and the intensity of ATG5 expression in zone II hepatocytes (P = .029). Overexpression of ATG5 in hepatocytes was significantly associated with mild portal tract fibrosis (P = .038) and mild lymphocytic infiltrates (P = .005).
Conclusion: ATG5 appears to contribute to the pathogenesis of NC in Egyptian infants. These findings may provide a basis for further research into novel diagnostic and therapeutic strategies.

Abstract Background & Objective: Graves’ disease (GD) is a common autoimmune thyroid disorder characterized by thyroid hormone hypersecretion and autoantibody formation against the thyrotropin receptor (TRAb). Interleukin-35 (IL-35), a novel immunosuppressive cytokine of the IL-12 family secreted primarily by regulatory T and B cells, has been implicated in the modulation of autoimmune responses. Transforming growth factor β (TGF-β) is a cytokine with immunoregulatory properties that plays a central role in T-regulatory cell differentiation. This study aimed to investigate serum IL-35 and TGF-β levels in Iraqi patients with GD and assess their association with disease severity, clinical manifestations, and response to carbimazole therapy.
Methods: A total of 103 participants were enrolled, including 66 patients with GD (mean age, 41.6 [SD, 13.95] years) and 37 healthy controls (mean age, 37.43 [SD, 10.25] years). Serum IL-35 and TGF-β concentrations were measured using enzyme-linked immunosorbent assay (ELISA).
Results: IL-35 levels were significantly reduced in untreated GD patients compared with healthy controls and partially increased after carbimazole therapy (P < .001). TGF-β levels were highest in untreated patients and declined after treatment (P < .001). IL-35 showed no correlation with FT3, FT4, or TRAb but was elevated in patients with disease duration longer than 5 years (P = .046) and in those with severe exophthalmos (P = .03). TGF-β levels were inversely correlated with FT3, FT4, and TRAb (P < .05) and were higher in carbimazole nonresponders and in patients with severe exophthalmos (P < .05).
Conclusion: IL-35 may serve as a promising biomarker for monitoring disease activity, prognosis, and therapeutic response in patients with GD.

Abstract Background & Objective: Community-acquired Staphylococcus aureus bacteremia (CA-SAB) is associated with substantial morbidity, mortality, and healthcare costs. This study aimed to identify clinical and laboratory factors associated with in-hospital mortality among patients with CA-SAB.
Methods: This retrospective cross-sectional study was conducted at a tertiary referral hospital in Tehran, Iran. Adult patients with positive blood cultures for S. aureus who met CA-SAB criteria were included. Demographic, clinical, and laboratory data were collected from medical records. The primary outcome was in-hospital mortality. Univariate and multivariate logistic regression analyses were performed to assess associations with mortality.
Results: A total of 114 patients with CA-SAB were included. No significant association was observed between underlying comorbidities and mortality. Although methicillin-resistant S. aureus (MRSA) infection was associated with a higher mortality rate, this difference was not statistically significant (P = .32). Multivariate analysis revealed that older age (odds ratio [OR], 1.053; 95% CI, 1.012–1.095; P = .01), elevated C-reactive protein (CRP) levels (OR, 1.016; 95% CI, 1.005–1.028; P < .01), and lower serum albumin levels (OR, 0.249; 95% CI, 0.097–0.642; P < .01) were independently associated with in-hospital mortality.
Conclusion: Although age was not significant in univariate analysis, it emerged as a significant predictor after adjustment for other variables. Routine laboratory parameters such as CRP and albumin may serve as valuable prognostic indicators. Early identification of high-risk patients using these markers could inform timely interventions and improve outcomes in CA-SAB.

Abstract Background & Objective: This study aimed to evaluate the expression patterns of epidermal growth factor receptor (EGFR) in patients with triple-negative breast cancer (TNBC) in Kerman, Iran, and investigate its association with various clinicopathological factors.
Methods: A retrospective cross-sectional study was conducted on 54 TNBC patients diagnosed between 2013 and 2022. Immunohistochemistry (IHC) was performed to assess EGFR expression levels in tumor tissue samples. Patients were classified as EGFR-positive or EGFR-negative based on IHC staining results. Clinicopathological data, including age, tumor grade, vascular invasion, lymph node involvement, Ki-67 proliferation index, presence of necrosis, ductal carcinoma in situ (DCIS), and microcalcifications, were collected. Statistical analyses were performed to examine the association between EGFR expression and clinicopathological variables.
Results: EGFR expression was positive in 61.1% of the patients. A significant association was found between EGFR positivity and higher tumor histologic grade (P = 0.045), with 69.7% of EGFR-positive patients exhibiting grade III tumors compared to 38.1% in the EGFR-negative group. Although not statistically significant, EGFR-positive patients tended to be younger (median age 44 years) than EGFR-negative patients (median age 52 years) (P = 0.157). The Ki-67 proliferation index was higher in EGFR-positive patients (median 60.0%) compared to EGFR-negative patients (median 47.5%).
Conclusion: EGFR expression is significantly associated with higher tumor grade, suggesting a correlation with more aggressive tumor behavior. EGFR may serve as a potential prognostic marker and therapeutic target in TNBC. Further research with larger cohorts is recommended to validate these findings and explore the implications of EGFR-targeted therapies in TNBC management.

Abstract Background & Objective: Programmed death ligand-1 (PD-L1) plays a critical role in tumor immune evasion, particularly in Non-Hodgkin’s B-cell lymphomas (NHL). This study aimed to evaluate PD-L1 expression across various NHL immunophenotypes and assess its correlation with clinical and demographic parameters.
Methods: In this cross-sectional, descriptive-analytical study, 71 formalin-fixed, paraffin-embedded tissue blocks diagnosed with Non-Hodgkin’s B-cell lymphoma were retrieved from the pathology archives of Alzahra Hospital and Seyed-al Shohada (Omid) Hospital in Isfahan (2019–2020). PD-L1 expression was assessed immunohistochemically using tumor proportion score (TPS), combined proportion score (CPS), and immune cell (IC) score. Statistical analysis was performed using the Mann-Whitney U and Kruskal-Wallis tests, with p < 0.05 considered statistically significant.
Results: Among the 71 patients, 67.6% were male, with a mean age of 52.61 ± 18.43 years. Diffuse large B-cell lymphoma (DLBCL) was the most common subtype, accounting for 52.1% of cases. PD-L1 expression was significantly higher in females (TPS: 18.13 ± 9.73; CPS: 28.22 ± 13.31) compared to males (TPS: 4.42 ± 3.56; CPS: 12.08 ± 10.14) (p = 0.040, p = 0.022). No significant differences in PD-L1 expression were observed across age groups. DLBCL demonstrated significantly higher IC and CPS values compared to other subtypes (p < 0.05), while plasmacytoma and Burkitt lymphoma exhibited the lowest scores (e.g., immune score: 1.11 ± 0.11 for plasmacytoma). No statistically significant differences in TPS were noted among the different immunophenotypes (p = 0.119).
Conclusion: Elevated PD-L1 expression, particularly in immune cell scores, suggests potential utility in PD-1/PD-L1–targeted therapies for NHL. However, the prognostic significance of PD-L1 remains inconclusive, highlighting the need for further investigation into its role as a predictive biomarker in the clinical management of Non-Hodgkin’s B-cell lymphomas.

Abstract Background & Objective: Luminal B breast cancer (LBBC) is on the rise worldwide, with both incidence and mortality rates steadily increasing. Early detection proves difficult due to its aggressive characteristics, most notably its heightened proliferation rate and the complex interplay of molecular biomarkers, particularly in more advanced stages.
Methods: Data Sources: In the present study, we conducted an in-silico analysis of LBBC cell lines using the Gene Expression Omnibus (GEO) microarray dataset, which includes 30 LBBC and 11 normal samples. Analysis Tools: Differentially expressed genes (DEGs) were identified using RStudio. A series of analyses, including cancer data interrogation via pan-cancer analysis, eXpression2Kinases (X2K), and the Cancer Dependency Map (DepMAP), was carried out to elucidate the underlying signaling pathways, transcription factors (TFs), and kinases, as well as to perform stemformatics analysis. Protein–protein interaction (PPI) networks were reconstructed using STRING and Cytoscape, enabling the identification of co-expressed and hub genes through the cytoHubba plug-in.
Results: Of note, FGF2, EGFR, ADIPOQ, LIPE, MET, IGF1, FGF1, EGF, FGF7, and PPARG were identified as the top 10 hub genes; RELA, PPARG, CTCF, EGR1, and NFE2L2 were detected as predominant TFs in LBBC; and CDK1, CDK2, MAPK3, CSNK2A1, and MAPK14 were identified as potential biomarkers through hub gene clustering. Further analysis indicated hsa-mir-221-3p and hsa-mir-29a-3p as key miRNAs targeting LBBC-related genes.
Conclusion: Collectively, our findings highlighted LBBC-associated genes, TFs, miRNAs, and pathways as prospective biomarkers, providing insights into LBBC diagnosis and therapeutic approaches.

Abstract Background & Objective: Sinonasal melanoma is an aggressive malignancy with a poor prognosis, largely due to its propensity for local invasion and early metastasis. Diagnosis is often difficult, particularly in the absence of melanin pigmentation. Histopathological and immunohistochemical (IHC) evaluation is essential for confirmation. This report describes a diagnostically challenging case of amelanotic melanoma of the sinonasal region.
Case Presentation: A 56-year-old woman presented with a 5-month history of epistaxis, facial pain, and visual impairment of the left eye. Clinical examination revealed a mass in the left nasal cavity, initially diagnosed as sinonasal carcinoma. Histopathology suggested a differential diagnosis of non-Hodgkin lymphoma (NHL) and poorly differentiated squamous cell carcinoma (SCC). Imaging demonstrated a sinonasal tumor involving the left extraconal orbital wall and paranasal sinuses. A biopsy initially raised suspicion for NHL; however, IHC staining was negative for CD45, CD20, and CD3. Similarly, negative P40 and cytokeratin excluded SCC. Strong immunoreactivity for S100, HMB45, and Melan-A established the diagnosis of amelanotic melanoma.
Conclusion: Amelanotic melanoma of the sinonasal tract poses a significant diagnostic challenge due to nonspecific clinical features and lack of pigmentation. This case highlights the indispensable role of IHC in achieving a definitive diagnosis.

Abstract A rare condition, blastic plasmacytoid dendritic cell neoplasm, is classified as acute myeloid leukemia–related precursor neoplasms according to the World Health Organization’s 2022 classification. Previously thought to originate from natural killer cells, T cells, or monocytes, it is now believed to arise from plasmacytoid dendritic cells. The cause of this condition is not well understood, but it is often associated with the deletion of tumor suppressor genes such as RB1, CDKN1B, CDKN2A, and TP53.
The disease is aggressive and typically presents with initial cutaneous lesions that can progress to bone marrow involvement and leukemic dissemination. Flow cytometry/ immunohistochemistry can detect enhanced CD56, CD4, and CD123 expression. The differential diagnoses include myeloid sarcoma/acute myeloid leukemia, T-cell lymphoblastic leukemia/lymphoma, NK-cell lymphoma/leukemia, and certain mature T-cell lymphomas/leukemias. Although initial chemotherapy may elicit a patient response, relapse is common. Survival may be improved by stem cell transplantation.
This case report details the medical history of a 64-year-old woman who presented with a skin mass that exhibited slow growth over 6 months. The mass was firm on palpation. Extensive testing, including a bone marrow (BM) smear and biopsy, revealed numerous abnormal or blastic cells. Furthermore, flow cytometric analysis of the BM confirmed the presence of plasmacytoid dendritic cell–neoplastic precursor cells exhibiting CD4+ and CD56+ characteristics.

Abstract Congenital pulmonary airway malformation (CPAM) is a structural anomaly that occurs during development of the lower respiratory tract. We describe a 4-day-old male infant with this uncommon congenital anomaly. He presented with respiratory distress and low oxygen saturation. A chest radiograph showed infiltration in the right lower lobe, and a chest computed tomography (CT) revealed alveolar opacity with an air bronchogram pattern in the right lung along with mediastinal shift. The right lower lobe was surgically resected. Pathological examination showed an 8-cm, predominantly solid cut surface with a rare tiny cyst, consistent with a congenital cystic adenomatoid malformation (type 3). Congenital pulmonary airway malformations are the most common congenital parenchymal lung anomalies. Although their development is debated, it is believed to result from a halt in fetal bronchial tree growth between the sixth and seventh weeks of fetal life. Flaws in thyroid transcription factor 1 have also been proposed. With the widespread use of high-quality ultrasonography in modern obstetrics, it is now less likely for congenital pulmonary airway anomalies to remain undetected until adulthood. Early surgical excision is generally recommended. However, in asymptomatic infants, management remains controversial because either operative or non-operative approaches may be used later in life, particularly in light of complications such as the potential for mucinous adenocarcinoma with a lepidic-predominant pattern. Patients with this condition in neonatal intensive care units should be managed by a multidisciplinary team that includes pediatric surgeons, neonatologists, and radiologists.