Iranian Journal of Pathology

Abstract COVID–19–associated pulmonary aspergillosis (CAPA) is a complication of COVID-19. Galactomannan (GM) is a non-invasive test used to diagnose invasive aspergillosis. We collected the existing studies on the diagnostic value of GM to determine a GM level for predicting CAPA. All articles on the value of GM in CAPA diagnosis published until November 2023 were reviewed. The main databases were searched using the following keywords: “aspergillus”, “aspergillosis”, “SARS-CoV-2”, “COVID”, “2019 ncovnCOV”, “novel coronavirus”, “COVID-19”, “galactomannan”, and “CAPA”. Studies with reported levels of serum or BAL GM were included. Patients were classified into two groups: non-confirmed and proven aspergillosis. Finally, the receiver operating characteristic (ROC) curve analysis was used to determine a GM level to predict the likelihood of CAPA. A total of 26 articles were selected, of which 239 patients were included. A count of 123 patients (50%) were in the non-confirmed group and 124 (50%) patients were proven. The median serum GM was 0.51 in the non-confirmed group and 0.47 in the proven group (p= 0.73). The level of GM in BAL fluid was 0.10 in the non-confirmed and 2.80 in the proven group, which was statistically different (p<0.001). With 81.3 % sensitivity and 79.5% specificity, the BAL GM cut-off was 1.01 ODI. The results showed that BAL GM ≥1.01 can be used to predict CAPA. Serum GM did not show any predictive value in diagnosing CAPA. However, BAL GM level can be a reliable diagnostic test in patients with CAPA.

Abstract Background & Objective: Long noncoding RNAs (lncRNAs) are transcripts longer than 200 nucleotides, a major component of noncoding RNAs. Previous studies have shown the oncogenic role of various lncRNAs. This study aimed to explore the expression and prognostic value of ATB and SNHG16 in patients with hepatocellular carcinoma.
Methods: ATB and SNHG16 expression in tumor and adjacent normal tissues was identified using real-time quantitative PCR. In this study, patients were divided into 2 groups based on the expression level of each gene, and the correlation between expression level and clinicopathological features of patients with HCC was investigated. All data were analyzed using SPSS version 22.
Results: Of the lncRNAs examined in this study, ATB was expressed at significantly higher levels in tumor tissues. However, this overexpression was not associated with any clinicopathological features of HCC patients.
Conclusion: In this study, overexpression of ATB and SNHG16 was not associated with survival rate or clinicopathological features of patients with hepatocellular carcinoma.

Abstract Background & Objective: Cholangiocarcinoma (CCA) is a malignancy that accounts for approximately 3% gastrointestinal cancer. The aim of this study was to evaluate and compare the diagnostic value of CD56, SMAD4, CEA, and p53 biomarkers in diagnosing cholangiocarcinoma and its benign mimickers.
Methods: This retrospective cross-sectional study was conducted on 54 CCA specimens and 27 non-cancerous pancreatobiliary tissue samples diagnosed between 2018 and 2022. All specimens were evaluated using immunohistochemistry (IHC) staining for CD56, SMAD4, CEA, and p53 expression. The cut-off value of each marker was obtained from the respective kit instructions and previous studies. The results were analyzed using SPSS version 26. A significance level of less than 0.05 was considered statistically significant.
Results: Of the 81 specimens, the mean age in the case and control groups was 57.33 ± 11.99 and 44.7 ± 16.69 years, respectively, and 51 (63%) samples were obtained from male patients. We found that 39.5% had grade III p53 expression, 13.5% had grade II p53 expression, 41.9% had grade III CEA expression, and 9.8% had grade II CEA expression. Additionally, 17.3% were positive for CD56 expression, and 7.4% showed SMAD4 loss. There were significant associations between the expression of CEA (79.6%) and p53 (74%) in the CCA group (p-value < 0.05). However, SMAD4 loss and CD56 expression were not statistically significant.
Conclusion: Expression of CEA and p53 based on IHC staining is associated with the occurrence of CCA. However, SMAD4 and CD56 were not significantly associated with CCA. Further survival analysis and sensitivity and specificity assessments are needed to obtain more comprehensive results.

Abstract Background & Objective: Breast cancer (BC) can be categorized into 4 groups based on molecular and pathological evidence: Luminal A, Luminal B, HER2+ tumors, and triple-negative breast cancer (TNBC). TNBC has a poorer survival rate and a higher chance of recurrence and metastasis compared to other BC types, primarily due to its challenging treatment course. Claudin 4 (CLDN4), a transmembrane protein in tight junctions between cells, has been linked to poor prognosis and faster disease progression in these malignancies.
Methods: Patients previously diagnosed with TNBC and tested for CLDN4 overexpression were contacted for follow-up and to determine disease outcomes. The current health status, cause, and time of death (if applicable) were recorded. Patient files were accessed to obtain information on age, tumor size and grading, lymph node involvement, metastasis, Ki67, and CLDN4 expression.
Results: Patients with high CLDN expression showed a significantly lower mortality rate. However, after controlling for other covariates, the hazard ratio (HR) was 0.48 (95%CI= [0.13 – 1.27]) in the crude model for survival, 0.54 (95%CI = [0.2 – 1.43]) when adjusted for age at diagnosis, and 0.58 (95%CI = [0.18-1.82]) when adjusted for other covariates. CLDN4 was also not correlated with tumor metastasis (HR=0.64, p=0.203, in the crude model; HR=0.52, p=0.409, when adjusted for other covariates). Patients in the CLDN4 high group had a significantly higher number of tumors >2cm.
Conclusion: Although previous studies have shown that CLDN4 overexpression worsens TNBC prognosis and increases metastasis or recurrence, the current study found no such association.

Abstract Background & Objective: Acinetobacter baumannii is a globally recognized nosocomial pathogen capable of developing multidrug resistance. This study investigates antibiotic resistance patterns, evaluates common resistance genotypes, and explores the genetic relatedness of PDR A. baumannii clinical isolates from hospitals in the Middle Euphrates region of Iraq.
Methods: Fourteen PDR A. baumannii isolates were obtained and subjected to antimicrobial susceptibility testing using the Vitek-2 compact system. Resistance genes were identified via conventional PCR, and clonal relationships were analyzed using multilocus sequence typing (MLST).
Results: Among 175 A. baumannii isolates, 8% (14/175) were classified as PDR strains, exhibiting resistance to all tested antibiotics. TEM was the most prevalent resistance gene (50%), followed by CTX-M (43%). SHV, IMP, KPC, OXA-48, and Mcr-1 genes were absent in all PDR isolates. MLST analysis identified five sequence types (STs): ST2, ST218, ST138, ST123, and ST460, with ST2 being the most common (50%).
Conclusion: The high prevalence of PDR A. baumannii strains in Iraq highlights the need for enhanced antibiotic surveillance. A comprehensive molecular investigation is necessary to mitigate the spread of these resistant pathogens.

Abstract Background & Objective: Breast cancer (BC) is the most common type of malignant neoplasm and is the primary cause of mortality among women aged 45 to 55 years. Studies indicate that cancer displays irregular metabolic patterns in contrast to normal tissue. Furthermore, there is compelling evidence supporting the significant role of peroxisomes in the intricate metabolic processes of cancer. Peroxisomal biogenesis factors (PEXs), which are peroxisomal proteins, control activities such as the degradation and biogenesis of peroxisomes. Hence, the correlation between peroxisomal biogenesis factor expression and BC was explored, to introduce key proteins and potential biomarkers by analyzing.
Methods: This study utilized UALCAN, GenExMiner v4.8, Metascape, STRING, TIMER, the Kaplan-Meier plotter, The Human Protein Atlas, MirTarBase, and cBioportal.
Results: The transcriptional levels of PEX6/7/10/11B/13/16 in BC tissues were significantly elevated, whereas the transcriptional levels of PEX2/3/5/11A/12/19 were significantly reduced. High expression levels of PEX 2/3/10/12/11G /26/13/16/14 were significantly related to shorter relapse-free survival, and higher mRNA expression of PEX 11B/11G/11A/12/19 was significantly associated with longer overall survival of BC patients. We identified has-miR-4318 and has-7106-3p as more correlated miRNAs with the PEX family.
Conclusion: Our results may provide novel insights for the selection of therapeutic targets and prognostic biomarkers for BC. 

Abstract Background & Objective: Clear cell renal cell carcinoma (CCRCC) is the most common type of renal cancer. Limited studies have been conducted about factors affecting the survival of patients with CCRCC. In this study, we aimed to evaluate the association between histologic growth patterns (HGPs) and some pathologic features and survival in CCRCC.
Methods: This cross-sectional study evaluated the association between HGPs and other pathologic features and the survival of 145 patients with CCRCC after nephrectomy in Emam-Reza Hospital (Mashhad, Iran) from 2012 to 2022. Two expert pathologists assessed HGPs and other pathologic features, like cytopathologic changes. All analyses were performed using IBM SPSS version 26 software. A P value less than 0.05 was considered statistically significant.
Results: In the current study, we assessed the association of the 6 most prevalent growth patterns with the patient’s survival. Some clinicopathologic features like tumor stage and grade, tumor size, and necrosis are negatively linked with survival. Two important cytologic features, including sarcomatoid and rhabdoid, were also associated with survival time in patients with CCRCC (P values < 0.05). Regardless of the nuclear grade of the tumor, some patterns like solid sheet, papillary, and thick trabecular were associated with lower survival.
Conclusion: Some HGPs are significantly associated with the patient’s survival in CCRCC. A greater variety of patterns within each specimen has been associated with a reduced survival rate. The impact of HGPs on patient survival may be as significant as the nuclear grade.

Abstract Background & Objective: Melanoma is one of the most common types of skin cancer with an annually increasing mortality rate. Cyclooxygenase-2 (COX-2) plays an imperative role as a cancer biomarker in the biosynthesis of prostaglandin and thromboxane during inflammatory reactions. Its overexpression has been demonstrated in various cancer types, including melanoma. However, its clinicopathological association with melanoma is controversial. We aimed to immunohistochemically evaluate COX-2 expression in malignant melanoma (MM) tumors.
Methods: In this cross-sectional retrospective study, blocks from patients with MM who were referred to Rasool-Akram and Razi hospitals between 2011 and 2020 were collected and immunohistochemically evaluated using COX-2 antibody. The intensity and percentage of COX-2 expression was determined in tumoral tissues, and its association with clinical and histological features of patients were evaluated.
Results: A total of 39 patients diagnosed with MM were included in this study, of whom 20 (51.3%) were male and 19 (48.7%) were female, with an average age of 57.28 ± 14.37 (range 14-87 years). The most common histological subtypes were acral melanoma (30.8%) and nodular melanoma (20.5%). The most common locations of tumor involvement were the lower (33.3%) and upper limbs (23.1%). Ulcers and vascular-lymphatic invasion were observed in 33.3% and 5.1% of cases, respectively. 38.5% of tumors were in level IV according to Clark’s level. Elastosis was present in 13% of samples. Approximately 87% of MM samples showed COX-2 expression, 61.5% of which were strong. There was a significant association between COX-2 expression and tumor location (P = .04).
Conclusion: Our findings highlight that the COX-2 protein is considerably expressed in MM tumors. Therefore, therapeutic strategies with the aim of targeting COX-2 might be considered in the prevention or treatment of MM. However, it remains to be explored whether COX-2 might be a prognostic marker of MM.

Abstract Background & Objective: Systemic Lupus Erythematosus (SLE) is an autoimmune disease characterized by immune dysregulation, autoantibody production, and organ damage, notably in the kidneys. Cytokine imbalances contribute to SLE's diverse clinical presentations. This study investigated the roles of interleukin-8 (IL-8) and its receptor, CD181 (CXCR1), in SLE pathogenesis, specifically focusing on their association with hemolytic anemia, a severe complication.
Methods: This research investigates the role of interleukin-8 (IL-8) and its cognate receptor, CXCR1 (CD181). It was analyzed clinical and demographic data from 250 SLE patients and quantified IL-8 and CD181 mRNA and protein expression in samples from patients with active SLE, inactive SLE, and SLE complicated by hemolytic anemia, comparing them to healthy controls.
Results: Of the 250 samples, 84% were from SLE patients, with 67% in the active disease phase. Significant upregulation of both IL-8 and CD181 mRNA and protein was observed in SLE patients compared to controls. Specifically, mRNA expression was significantly elevated in active SLE (p=0.0001) and inactive SLE (p=0.01). Notably, IL-8 mRNA expression was significantly higher in SLE patients with hemolytic anemia (p<0.0001) compared to those without (p<0.01(.
Conclusion: These findings suggest that the IL-8/CD181 axis plays a crucial role in the inflammatory processes and tissue damage associated with SLE, particularly in the development of hemolytic anemia.

Abstract Background & Objective: Melanomas have diverse pathological features that mimic other tumors, such as lymphoma, sarcoma, and even poorly differentiated carcinoma. The most recently identified variant, the plasmacytoid variant, is an uncommon variant that can appear as a solitary tumor or a metastatic disease. Due to its rarity, the epidemiologic profile of this variant is not well characterized. This case report illustrates a diagnostic challenge of plasmacytoid cell mimicker, which is rarely found in daily practice.
Case Presentation: A 49-year-old man presented with multiple subcutaneous soft tissue nodules in the thoracic area and multiple pathological fractures in the left distal humerus and distal ulna. Clinical and radiological findings were suggestive of metastatic bone disease with differential diagnosis of multiple myeloma. Fine needle aspiration biopsy and histopathological findings were suggestive of multiple myeloma with differential diagnoses of metastatic carcinoma, rhabdomyosarcoma, and amelanotic melanoma. Thus, immunostaining for CD138, CK, desmin, vimentin, S-100, and HMB45 were requested and the results were compatible with the final diagnosis of amelanotic plasma melanoma.
Conclusion: It is crucial to consider melanoma as one of the differential diagnoses of a tumor with plasmacytoid feature and CD138 positive staining as it can mimic multiple myeloma as demonstrated in this case report.

Abstract Background & Objective: Heterotopic pancreas (HP) or ectopic pancreas is the occurrence of pancreatic tissue in an atypical location with absence of any neurovascular or anatomic connection with the normal pancreas. In an autopsy series, the incidence of this embryologic anomaly is 0.55% to 13.7% of patients. Gallbladder is an extremely rare site for ectopic pancreatic tissue with approximately 40 documented cases.
Case Presentation: We hereby report a case of incidental discovery of ectopic pancreatic tissue in the excised gallbladder from a 27-year-old female who presented with nausea, vomiting, and abdominal pain intermittently. The gallbladder lumen was filled with biliary sludge containing a single gallstone. Histopathology revealed chronic cholecystitis along with a tiny focus of ectopic pancreatic tissue comprising only pancreatic acini.
Conclusion: This case highlights that histopathology should be mandatory for all excised gallbladder specimens and that this entity should be considered among the differentials for nodular/polypoidal gallbladder lesions. Although the cases where the ectopic pancreas is discovered incidentally do not have much clinical significance, this may prevent the patient from undergoing more aggressive treatment reserved for conditions like pancreatitis or malignancy in cases where the ectopic pancreas mimics a malignancy.

Abstract Cutaneous pseudolymphomas (PSLs) as lymphocytic infiltrates are benign lesions that clinically and histopathologically mimic lymphomas. Miliarial type lymphocytoma cutis is an uncommon type of pseudolymphoma that is characterized by multiple semi-translucent micropapules on the sun-exposed regions. We present a 61-year-old woman who was admitted to our clinic with diffuse, sand-like, and erythematous micropapules on her face. Microscopic findings revealed nodular lymphoid aggregation, with the germinal center formation consisting of polyclonal lymphoid infiltrate confirmed by Immunohistochemistry (IHC) studies. According to this clinicopathological correlation, the miliarial type pseudolymphoma was confirmed and she was treated with topical corticosteroid ointment with a good response.

Abstract Background: Sclerosing angiomatoid nodular transformation of the spleen (SANT) is a rare, benign vascular lesion predominantly described in adults. Pediatric cases are exceptionally uncommon and present a diagnostic challenge due to nonspecific clinical presentations and imaging findings.
Case Presentation: We report the case of a 12-year-old boy presenting with recurrent abdominal pain localized around the umbilicus, accompanied by intermittent nausea over a three-month period. Physical examination revealed mild tenderness without guarding. Laboratory findings were unremarkable. Abdominal ultrasound demonstrated a hypoechoic splenic lesion, further evaluated by multidetector computed tomography (MDCT), which revealed a heterogeneous hypodense mass in the spleen. The patient underwent partial laparoscopic splenectomy. Histopathological examination showed a nodular architecture with fibrous bands, capillary-like vascular channels lined by endothelial cells, and a lymphoplasmacytic infiltrate. Immunohistochemical staining was positive for CD31, CD34, and CD8, supporting the diagnosis of SANT.
Conclusion: Although benign, SANT can mimic more aggressive splenic pathologies. This case underscores the importance of considering SANT in the differential diagnosis of splenic masses in pediatric patients and highlights the role of histopathology and immunohistochemistry in achieving a definitive diagnosis.