Iranian Journal of Pathology

Abstract Background & Objective: High-sensitivity cardiac troponin T (hs-cTnT) has emerged as a critical biomarker in cardiovascular diseases, particularly in congestive heart failure (CHF). This systematic review and meta-analysis aimed to assess the association between hs-cTnT levels and clinical outcomes in patients with CHF.
Methods: A comprehensive literature search was performed across multiple databases to identify studies evaluating the relationship between hs-cTnT levels and clinical outcomes in CHF. Eligible studies reported hazard ratios (HRs) or odds ratios (ORs) for all-cause mortality, cardiovascular mortality, or cardiovascular hospitalization.
Results: Elevated hs-cTnT levels were significantly associated with adverse outcomes. The pooled HR and OR for all-cause mortality were 1.70 (95% CI, 1.49–1.94) and 6.19 (95% CI, 3.88–9.86), respectively. For cardiovascular mortality, the pooled HR was 1.59 (95% CI, 1.38–1.83) and the pooled OR was 6.87 (95% CI, 3.93–12.01). For cardiovascular hospitalization, the pooled HR was 1.56 (95% CI, 1.42–1.70) and the pooled OR was 4.32 (95% CI, 2.22–8.39).
Conclusion: Elevated hs-cTnT levels are strongly associated with an increased risk of all-cause mortality, cardiovascular mortality, and cardiovascular hospitalization in patients with CHF. These findings highlight the prognostic value of hs-cTnT in the clinical management of heart failure.

Abstract Background & Objective: Whole Slide Imaging (WSI) has emerged as a transformative technology in the fields of clinical diagnostics, medical education, and pathology research. By digitizing entire glass slides into high-resolution images, WSI enables advanced remote collaboration, the integration of artificial intelligence (AI) into diagnostic workflows, and facilitates large-scale data sharing for multi-center research.
Methods: This paper explores the growing applications of WSI, focusing on its impact on diagnostics through telepathology, AI-powered diagnoses and precision medicine, and educational advancements. In this report, we will highlight the profound impact of WSI and address the challenges that must be overcome to enable its broader adoption.
Results & Conclusion: Despite its many advantages, challenges such as infrastructure limitations and regulatory issues need to be addressed for broader adoption. The future of WSI lies in its ability to integrate with cloud-based platforms and big data analytics, continuing to drive the digital transformation of pathology.

Abstract Background & Objective: Bladder cancer is the fourth most prevalent malignancy and lacks reliable biomarkers for predicting tumor stage, grade, and clinical outcomes. This study aimed to evaluate the association between thrombomodulin (TM)–positive cell rate (PR) and tumor grade, stage, and recurrence in patients with bladder cancer.
Methods: This prospective observational pilot study was conducted at the Urology Clinic of Sina Hospital, Tehran, between March and December 2022. A total of 51 patients diagnosed with bladder cancer following cystoscopy and transurethral resection of bladder tumor (TURBT) were enrolled. Of these, 11 patients with stage T2 disease underwent radical cystectomy. TM expression was assessed by immunohistochemical staining, and the PR score was calculated. The remaining 40 patients underwent follow-up cystoscopy 3 months post-TURBT to assess for recurrence or progression. Statistical analyses were performed using SPSS version 26, with comparisons of quantitative variables conducted using ANOVA and t tests.
Results: The mean age of participants was 66.73 ± 11.00 years, and 46 were male. The mean TM PR value was 25.51 ± 6.24. No significant differences in TM PR values were observed among different tumor grades (p = 0.144) or stages (p = 0.815). Additionally, there were no significant differences in TM PR values or PR scores between patients with and without recurrence at 3-month follow-up cystoscopy (p = 0.144 and p = 0.085, respectively).
Conclusion: TM PR values did not correlate with tumor grade, stage, or recurrence in this cohort of bladder cancer patients. Further studies with larger sample sizes and longer follow-up periods are warranted.

Abstract Background & Objective: Although the concordance between immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH) is generally high for HER2 scores of 3+ and 1+, discrepancies remain in cases scored as IHC 2+. This study aimed to evaluate HER2/neu gene amplification using FISH in breast cancer patients with IHC 2+ and to examine associated clinicopathological characteristics.
Methods: This retrospective study included tissue samples from 369 women diagnosed with invasive ductal carcinoma of the breast and an equivocal HER2 IHC score (2+). These samples were further assessed for HER2 gene amplification using FISH. Demographic and clinicopathological data were collected and analyzed.
Results: The mean age of patients was 51.6 ± 2.6 years. FISH analysis revealed no HER2 amplification in 72.6% of IHC 2+ cases, while 27.4% demonstrated amplification. HER2 amplification was significantly associated with younger age, higher histological grade, lymph node involvement, larger tumor size, and reduced survival rate. No significant association was observed between HER2 amplification and margin involvement.
Conclusion: HER2 amplification is a significant predictor of aggressive tumor behavior and may necessitate targeted therapy. In cases with IHC 2+, both FISH results and relevant clinicopathological features should be considered prior to initiating trastuzumab treatment.

Abstract Background & Objective: Oral squamous cell carcinoma (OSCC) accounts for over 90% of oral cancers. Cytokeratin 19 (CK19), produced by suprabasal epithelial cells, reflects alterations in cellular behavior and has been associated with premalignant changes in the oral epithelium. This study aimed to evaluate the expression of CK19 in OSCC and oral epithelial dysplasia (OED) and its potential role in oral carcinogenesis.
Methods: A total of 50 samples were analyzed, including 30 OSCC cases and 10 OED cases obtained from the archives of the Department of Pathology, as well as 10 normal oral mucosa samples collected from clinically healthy areas adjacent to mucocele lesions. CK19 expression was assessed using immunohistochemistry
Results: Positive immunoreactivity for CK19 was observed in 90% (27/30) of OSCC samples. CK19 expression in the OSCC group was significantly higher compared to the OED and normal mucosa groups. Among OSCC cases, grade III tumors exhibited stronger CK19 expression than grades I and II. Additionally, CK19 expression in grade II OSCC was higher than in the OED group.
Conclusion: The progressive increase in CK19 expression from normal mucosa to OED and OSCC supports its involvement in oral mucosal carcinogenesis. Moreover, higher CK19 expression correlated with increasing tumor grade and decreasing cellular differentiation, suggesting its potential value as a diagnostic and prognostic biomarker in OSCC.

Abstract Background & Objective: Mucormycosis has emerged as a severe complication in COVID-19 patients, particularly among those with uncontrolled diabetes and those receiving corticosteroid therapy. The infection's tendency to spread from the sinuses to the orbit and central nervous system (CNS) significantly increases morbidity and mortality. This study aimed to identify clinical risk factors and outcomes associated with disease severity and mortality in COVID-19–associated mucormycosis (CAM), with a focus on disease progression to orbital and CNS involvement.
Methods: A total of 180 confirmed CAM patients were enrolled and classified into three groups based on disease extent: sinus-only, sinus with orbital involvement, and sinus with both orbital and CNS involvement. Data were collected on demographics, clinical history, laboratory findings, imaging results, treatment modalities, and outcomes.
Results: Of the 180 patients, 63.3% had sinus-only involvement, 23.9% had sinus and orbital involvement, and 12.8% had sinus, orbital, and CNS involvement. Uncontrolled diabetes was observed in 38% of patients and was more prevalent in those with extensive disease. Corticosteroid use was significantly associated with disease severity (p = 0.002). Invasive procedures, such as orbital exenteration, were significantly linked to CNS progression (p < 0.05). The overall mortality rate was 31% (55 of 180 patients).
Conclusion: Uncontrolled diabetes and corticosteroid therapy are major risk factors for severe CAM. Extension of mucormycosis beyond the sinuses, particularly to the orbit and CNS, is associated with poor clinical outcomes and often requires aggressive surgical management. Early diagnosis and prompt intervention are essential to improve survival in these patients.

Abstract Background & Objective: Subtyping non–small cell lung carcinoma (NSCLC) into adenocarcinoma (ADC) and squamous cell carcinoma (SCC) is crucial for selecting appropriate molecular tests, as driver mutations are often subtype-specific. This study aimed to evaluate the utility of TTF-1, Napsin A, p40, and p63 immunohistochemical (IHC) markers in subtyping NSCLC on small biopsies, with the goal of identifying a minimal marker panel.
Methods: This retrospective, cross-sectional study was conducted at Kasturba Medical College, Mangalore, from January 2014 to December 2020. All NSCLC cases diagnosed during the study period were included. Immunohistochemical expressions of TTF-1, Napsin A, p40, and p63 was evaluated and correlated with morphological findings.
Results: Ninety-five NSCLC cases were included: adenocarcinoma (n = 35), squamous cell carcinoma (n = 57), and NSCLC-not otherwise specified (NOS) (n = 2). IHC reclassification based on marker expression resulted in six ADC cases retyped as SCC and eight SCC cases retyped as ADC. TTF-1 and Napsin A expression were significantly associated with adenocarcinoma (p < 0.001), while p40 and p63 expression were significantly associated with SCC (p < 0.001).
Conclusion: IHC is essential in overcoming the diagnostic limitations of small biopsy specimens, especially in morphologically heterogeneous tumors. A minimal panel comprising TTF-1 and p40 is sufficient for accurate subtyping of NSCLC and can help preserve tissue for downstream molecular testing.

Abstract Background & Objective: miR-196b, HOXA9, GFI1, and PIM1 are key factors involved in cellular signaling pathways that contribute to the pathogenesis of malignancies, including acute myeloblastic leukemia (AML). Given their critical roles in AML progression, the present study aimed to investigate the gene expression levels of HOTAIRM1, miR-196b, HOXA9, GFI1, and PIM1 in AML patients compared to healthy controls.
Methods: A total of 30 AML patients and 10 healthy volunteers were enrolled in this study. Peripheral blood and bone marrow mononuclear cells were isolated using Ficoll-Paque density gradient centrifugation. Gene expression levels of HOTAIRM1, miR-196b, HOXA9, GFI1, and PIM1 were assessed using real-time quantitative PCR (RQ-PCR). Statistical analyses were performed using Student’s t-test, one-way ANOVA, and Pearson correlation tests.
Results: The expression levels of HOTAIRM1, miR-196b, HOXA9, and GFI1 were significantly elevated in AML patients compared to healthy controls. Furthermore, t-test analysis revealed that the expressions of HOTAIRM1, HOXA9, and GFI1 significantly differed between AML-M3 and non-M3 AML subtypes.
Conclusion: These findings suggest that the investigated markers, particularly HOTAIRM1, HOXA9, and GFI1, may serve as potential clinical biomarkers for monitoring AML progression and could be valuable targets for early detection or therapeutic intervention.

Abstract Background & Objective: CD58 and ADAM10 have been implicated in leukemia progression and chemoresistance; however, their specific roles in acute lymphoblastic leukemia (ALL) and chronic lymphocytic leukemia (CLL), particularly under chemotherapeutic pressure, remain insufficiently characterized. This study aimed to assess the expression of CD58, an immune adhesion molecule, and ADAM10, a metalloproteinase, in ALL and CLL patients undergoing chemotherapy, and to explore their potential involvement in immune evasion, niche-mediated survival, and chemoresistance mechanisms.
Methods: Peripheral blood mononuclear cells (PBMCs) were isolated from 50 patients with ALL, 50 with CLL, and 30 healthy controls. Expression levels of CD58 and ADAM10 were analyzed by quantitative reverse transcription PCR (qRT-PCR) and flow cytometry. Chemotherapy regimens included vincristine (VCR), methotrexate (MTX), and doxorubicin (DOXO).
Results: ADAM10 mRNA expression was significantly upregulated in ALL patients treated with VCR+MTX (p<0.0001) and DOXO (p=0.001), with corresponding protein overexpression observed in both ALL (p<0.0001) and untreated CLL patients (p<0.0001). A significant difference in ADAM10 levels was noted between ALL and CLL cohorts (p=0.001). CD58 mRNA and protein expression were markedly increased in ALL patients receiving VCR+MTX (p<0.0001), whereas untreated CLL patients exhibited no significant alterations.
Conclusion: CD58 and ADAM10 are differentially regulated in ALL under chemotherapy, supporting their roles in immune evasion and microenvironmental survival. The constitutive overexpression of ADAM10 in CLL suggests its involvement in chronic leukemic pathogenesis. These findings highlight CD58 and ADAM10 as potential therapeutic targets for overcoming chemoresistance in lymphoid malignancies.

Abstract Background & Objective: Tumor-to-tumor metastasis is a rare phenomenon in which one primary tumor metastasizes into another histologically distinct tumor. This report presents a unique case of breast carcinoma metastasizing to a pheochromocytoma, posing significant diagnostic and therapeutic challenges.
Case Presentation: A 71-year-old woman with a history of breast carcinoma—status post mastectomy 7 years prior—presented with elevated levels of cancer antigen 15-3 (CA15-3), raising suspicion of disease recurrence or metastasis. Imaging studies revealed a mass in the adrenal gland. Surgical excision of the adrenal lesion was performed, and subsequent histopathological and immunohistochemical analyses confirmed the coexistence of two distinct tumor components: primary pheochromocytoma and metastatic breast carcinoma.
Conclusion: Although tumor-to-tumor metastasis is exceedingly rare, awareness of this entity is crucial for accurate diagnosis and effective treatment planning. This case underscores the importance of considering prior malignancies in the differential diagnosis of new adrenal masses and highlights the complexities involved in managing a hormone-secreting neoplasm concurrently harboring metastatic disease.

Abstract Background & Objective: This study presents a rare case of hydatid cysts involving the liver, spleen, and peritoneum, in which clinical features and radiologic findings initially raised strong suspicion for abdominal malignancy with peritoneal seeding.
Case Presentation: A 64-year-old man presented with vague epigastric pain, weight loss, and iron deficiency anemia. Abdominal ultrasonography revealed multiple splenic lesions suggestive of hydatid cysts. Hydatid serology was negative. Chest CT was unremarkable. Abdominal and pelvic CT showed splenomegaly with cystic lesions, including a calcified cyst in segment VI of the liver. Numerous hypodense peritoneal nodules were identified, particularly in the mid-omentum and supraumbilical region. Differential diagnoses included hydatid disease, primary peritoneal neoplasms, and peritoneal metastases. Due to anemia, weight loss, and the suspicion of peritoneal carcinomatosis, hydatid disease alone could not fully account for the findings, prompting further diagnostic evaluation. Endoscopy and colonoscopy were unremarkable. The patient underwent exploratory laparotomy and splenectomy, along with partial omentectomy where hydatid involvement was suspected. Postoperatively, he was treated with albendazole 800 mg daily and discharged on postoperative day three. At 3- and 6-month follow-ups, the patient reported resolution of abdominal pain, and physical examinations were normal.
Conclusion: Peritoneal hydatid disease is rare and can mimic peritoneal carcinomatosis, leading to diagnostic uncertainty and treatment delay. Surgical excision followed by antiparasitic therapy remains the cornerstone of management.

Abstract Background & Objective: Our study was mainly aimed at identifying the cause, clinical course of the disease, its most dreaded complication pseudomyxoma peritonei and spread to adjacent structures. We have used IHC techniques to know the origin of the tumor where both appendix and ovary were involved.
Case Presentation: We have listed out and discussed in detail 5 cases, each of which have a different clinical course and variation in staging, grading and prognosis. One of the cases had mucin deposits in the ovary, for which IHC was done to confirm the origin of the tumor. Some of the findings were incidental and in others presence of mucin content in the appendix lumen raised clinical suspicion of spread to peritoneum and adjacent structures. Grading and staging is of prime importance as it determines the prognosis and management of the patient respectively.
Conclusion: A ruptured or perforated appendix must warrant for an immediate suspicion of pseudomyxoma peritonei which when untreated can lead to mucinous neoplasms in adjacent organs like ovary and colon. Pseudomyxoma Peritonei (PMP) with simultaneous appendix and ovarian neoplasm should be treated as primary appendiceal tumour. Grading and staging of mucinous neoplasm of appendix and Pseudomyxoma Peritoneii needs a unified approach for standardized diagnostic reporting.

Abstract Dear Editor,
 
Fibroepithelial polyps (FEPs), also known as fibroepithelial stromal polyps, are benign growths that arise from a combination of mesenchymal and ectodermal tissues. These lesions, while generally common—with an estimated prevalence of 46% in the general population—are rarely found on the vulva (1).
FEPs exhibit considerable variation in clinical presentation, ranging from small wart-like projections to large pedunculated tumors (2,3). They may appear as solitary or multiple lesions and can occur synchronously on both sides of the vulva. Although vulval FEPs are typically small (usually <5 mm), a few cases of unusually large lesions have been reported (1,2,4–6).

Abstract Dear Editor,
 
Tubular adenomas are rare, comprising 0.13% to 1.7% of all benign breast neoplasms (1). While the tumor size varies between 1 cm and 7.5 cm, it seldom surpasses 5 cm, with only a very few reports of ‘giant tubular adenoma’ are on the record. We present a case of giant tubular adenoma in a young female along with a brief discussion on differential diagnoses and diagnostic difficulties in differentiating them from other fibroepithelial and benign proliferative breast lesions. This case represents the third-largest giant tubular adenoma documented in an adolescent to date, with a size of 12×10×8 cm, and adds to the growing but still limited body of literature in this regard. Additionally, this report consolidates previously scattered data by including a comparative summary of clinicopathological attributes of all published giant tubular adenoma cases [Table 1] (2-10).