Histology and histopathology Vol.40, nº6 (2025)

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    Ferroptosis: A key regulator and potential target for tissue injury
    (Universidad de Murcia, Departamento de Biologia Celular e Histiologia, 2025) Liu, Ruihan; Luo, Qing; Song, Guanbin
    The maintenance of iron homeostasis is essential for proper body function. A growing body of evidence suggests that iron imbalance is the common denominator in many tissue injuries, including acute, chronic, and reperfusion injuries. Ferroptosis, a novel form of programmed cell death due to metabolic abnormalities, has become increasingly recognized as an important process mediating the pathogenesis and progression of numerous tissue injuries, including cerebral, myocardial, lung, liver, kidney, and intestinal injuries. Therefore, a thorough understanding of the mechanisms involved in the regulation of ferroptosis might contribute to improvements in disease management. In this review, we summarize the importance of ferroptosis in various tissue injuries, discuss the potential targets of ferroptosis in the treatment of tissue injuries, and describe the current limitations and future directions of these novel treatment targets
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    Associations between BCL-2 expression and different histopathological prognostic factors in different molecular subtypes of invasive breast carcinoma of no special type
    (2025) Hassan, Wael Abdo; El Assmy, Mohamed; ElBanna, Ahmed Kamal; Harbieh, Ihab; Noufal, Noha; Lotfy, Hany; Shemais, Tarek Abdelaziz Hasan; Haikal, Ossama Ashour; Saber, Mostafa Magdy; Ali, Rehab Ibrahim
    Background. Breast cancer is heterogeneous and the existing prognostic classifiers are limited in accuracy, leading to the unnecessary treatment of numerous women. B-cell lymphoma 2 (BCL-2), an anti-apoptotic protein, has been proposed as a marker of poor prognosis, associated with resistance to therapy in most tumor types expressing BCL-2. In breast cancer, however, BCL-2 expression has been reported to be a favorable prognostic factor. This study aimed to describe the association between BCL-2 and other well-known pathological prognostic markers among different molecular sub-types of invasive breast carcinoma of no special type (IBC; NST). Methods. BCL-2 expression, as well as that of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2), were immunohistochemically (IHC) evaluated and compared with other pathological factors, including tumor size, grade, tumor-infiltrating lymphocytes (TILs), lymph-vascular invasion (LVI), and lymph node (LNd) metastasis, in 128 breast cancer cases diagnosed with IBC; NST. Moreover, we analyzed the correlation between BCL-2 expression and relapse-free survival (RFS) in all patients over a two-year period. Results. We found that BCL-2 expression had different pathological prognostic factor associations with different molecular subtypes of breast carcinoma. In the luminal A (i.e., hormonal receptor-positive and HER2-negative) and triple-negative subtypes, the expression of BCL-2 in tumor cells was significantly associated with tumor size, tumor grade, and TILs. BCL2-positive expression in luminal IBC; NST patients resulted in a significantly favorable two-year survival. Conclusion. BCL-2 expression in IBC; NST has different prognostic effects depending on the molecular subtype of the cancer. In cancers with a HER2-enriched phenotype, BCL-2 expression was a marker of poor prognosis, while in cancers with a hormone receptor-positive phenotype, BCL-2 expression had a better prognostic impact.
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    Cancer-associated fibroblast-secreted exosomes promote prostate cancer cell migration and invasion by the FGL1/SOX5 axis
    (Universidad de Murcia, Departamento de Biologia Celular e Histiologia, 2025) Kong, Lingquan; Wang, Xing; Li, Yu; Zhang, Xiansheng
    Exosomes secreted by cancer-associated fibroblasts (CAFs) play a critical role in cancer progression. This study aimed to explore the effects of CAF exosomes on prostate cancer (PC) cell metastasis. PC cells were treated with these exosomes, and their processes were evaluated using cell-counting kit-8 and Transwell assays. Exosome-regulated mRNAs were explored using quantitative real-time PCR. The relationship between FGL1 and SOX5 was analyzed using co-immunoprecipitation and fluorescence in situ hybridization (FISH) assays. The results of this study showed that exosomes derived from CAFs promoted PC cell viability, migration, and invasion. CAFs promoted PC cell viability and metastasis by releasing exosomes. Exosome treatment increased the levels of FGL1, which interacted with SOX5 and negatively regulated its expression. Rescue experiments demonstrated that CAF exosomes promoted the biological behaviors of PC cells by upregulating FGL1 and downregulating SOX5. Moreover, exosomes accelerated tumor growth by regulating the FGL1 level. In conclusion, CAF-derived exosomes promoted PC cell viability, migration, and invasion by elevating the FGL1/SOX5 axis, suggesting a novel strategy for the treatment of metastatic PC.
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    The role of the Ki-67 labelling index as an independent prognostic factor in indonesian glioma patients
    (Universidad de Murcia, Departamento de Biologia Celular e Histiologia, 2025) Dwianingsih, Ery Kus; Pranacipta, Sofia; Theresia, Emilia; Safitri, Sekar; Hartanto, Rachmat Andi; Malueka, Rusdy Ghazali
    Introduction. Gliomas are the most common type of brain tumor. However, interpreting glioma morphology is subjective, and identifying mitosis can be challenging. This can impact the determination of the patient's tumor grade, therapy, and prognosis. In addition, the Ki-67 expression level, which reflects the tumor cells' ability to proliferate, is closely related to the patient’s survival. This study aims to find a correlation between Ki-67 expression and the overall survival (OS) of glioma patients in the Indonesian population. Methods. Ninety-one glioma patients from Sardjito General Hospital were collected for formalin-fixed embedded paraffin (FFPE) samples, and the Ki-67 labeling index (LI) was calculated by determining the percentage of labeled nuclei per 1000 cells using a 40x objective lens in a randomized area (average method). The OS was calculated from the day of pathology diagnosis until death or the last follow-up (for censored cases). Kaplan-Meier survival analysis was used to analyze the OS. Results. Individuals aged ≥60 with high-grade tumors, infratentorial gliomas, and a Ki-67 LI ≥10% had a shorter OS. The p-values associated with these factors were 0.001, 0.018, and 0.006, respectively. In multivariate analysis, age and tumor grade did not significantly correlate with OS. Conclusion. Glioma patients with a Ki-67 LI ≥10% have a significantly shorter OS than those with a lower Ki-67 LI, indicating that Ki-67 LI is an independent prognostic factor in Indonesian glioma patients.
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    The prognostic value of H3 K27me3 in meningiomas: A review on current evidence and methodological challenges
    (2025) Pietrantoni, Alberto; Barresi, Valeria
    Meningiomas are the most common primary intracranial neoplasms. Although they mostly exhibit a benign course, some cases recur after surgery and show high morbidity and mortality rates. In addition to currently established prognostic factors, such as the extent of surgical resection and tumor grade assessed according to World Health Organization (WHO) criteria, the prognostic significance of the immunohistochemical loss of Histone 3 trimethylation in Lysine 27 (H3 K27me3) has emerged in meningiomas. This review examined original studies that analyzed the immunohistochemical expression of H3 K27me3 in meningiomas and its correlation with various features, including overall survival (OS), recurrence-free survival (RFS), and WHO grade. A literature search was conducted in PubMed for English-language publications up to July 8, 2024. Sixteen studies were included in this review. In summary, current evidence indicates that H3 K27me3 loss is more frequent in tumors exhibiting higher biological aggressiveness, as reflected by a significant association with a higher WHO grade, proliferative index, and prognostically unfavorable methylation classes. In addition, published studies consistently indicate a negative prognostic significance for progression-recurrence-free survival (PFS/RFS) in WHO grade 2 meningiomas and OS in WHO grade 3 tumors. However, the lack of a standardized definition for H3 K27me3 loss significantly hampers the incorporation of the H3 K27me3 immunohistochemical assay into routine practice to establish the prognosis of meningiomas.
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    Iron in the migraine brain
    (Universidad de Murcia, Departamento de Biologia Celular e Histiologia, 2025) Tepe, Nermin; Yemisci, Muge; Karatas, Hulya
    Iron, a vital element for numerous peripheral and central nervous system functions, is a key player in DNA synthesis, gene expression, myelination, neurotransmission, and mitochondrial electron transport. Iron has utmost importance in various neurological functions, including neurotransmitter synthesis and brain cell metabolism. Migraine is a neurogliovascular disorder in which neuroinflammation plays a crucial role. Iron deficiency has been associated with various neurological issues and could potentially influence migraine frequency or severity. However, the relationship between iron levels and migraine is not fully clear and necessitates further research. On the other hand, iron overload could also have negative effects, as excessive iron might contribute to oxidative stress and inflammation, which may impact migraine-related pathways. The interplay between iron levels and neuroinflammation might affect migraines. While iron deficiency could exacerbate inflammation or disrupt neurotransmitter balance, iron overload might increase oxidative stress and neuroinflammation. Comprehending this balance is fundamental, as both iron deficiency and overload can have detrimental effects on brain health and migraine symptoms. In this review, we will summarize the current interconnection between migraine, iron levels, and neuroinflammation that are currently under active investigation
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    Intratumoral T cells are associated with prognosis and chemotherapy benefit in gastric cancer
    (Universidad de Murcia, Departamento de Biologia Celular e Histiologia, 2025) Liu, Lu; Chen, Qianwen; He, Chen; Xie, Feilan; Su, Shengyuan; Wang, Lijun; Liu, Jintao
    Tumor-infiltrating lymphocytes (TILs) have been described in various malignancies and viewed as a sign of anti-tumor immunity, so they are frequently thought to be implicated in the prognosis of cancers. However, little information is available on the association of the distribution pattern of TILs with clinical outcomes in gastric cancer (GC). TIL densities at different regions were assessed immunohistochemically in 59 GC patients to analyze their relationship with clinicopathological characteristics. We found that GC patients in the high-density TIL group were significantly associated with reduced tumor invasion depth, absence of lymph node metastasis, earlier TNM stage, and improved progression-free survival (PFS). Both intratumoral CD3+ TILs and pathological T stage were identified as having an independent prognostic value. Additionally, GC patients with a high density of intratumoral CD3+ TILs were found to gain more benefit from chemotherapy. Overall, these results underscored the predictive power of intratumoral TILs in survival prognosis and chemotherapy benefit for GC
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    Histological and stereological insights into renal and adrenal changes in pregnant rats exposed to wood smoke-derived PM2.5
    (Universidad de Murcia, Departamento de Biologia Celular e Histiologia, 2025) Salinas, P.; Villarroel, F.; González Torres, C.; Lazcano, T.; Silva, J.; Maulen, A.; Rojas, E.
    Air pollution, particularly fine particulate matter (PM2.5), is a global health issue affecting millions. In southern Chile, firewood used for heating exacerbates pollution, especially in winter. This study examines the impact of wood smoke-derived PM2.5 on kidney and adrenal gland morphology in pregnant rats. It evaluates chronic PM2.5 exposure effects during pregestational and gestational periods in Sprague-Dawley rats. Pregnant rats were exposed to PM2.5 in Temuco, a city with high wood smoke pollution. Filtered and unfiltered air chambers simulated different exposure conditions. Histological and stereological analyses were conducted on rat kidneys and adrenal glands using systematic sampling and STEPanizer software. Findings showed significant changes in renal and adrenal morphology due to PM2.5 exposure. In the kidney, variations were observed in glomerular compaction, proximal convoluted tubules, and medullary rays. In the adrenal gland, the zona fasciculata showed decreased acidophilia and lipid content, reduced cytoplasmic homogeneity, and the appearance of empty spaces. These effects were more pronounced in rats exposed to unfiltered air during both pregestational and gestational periods. Wood smoke-derived PM2.5 exposure significantly impacts kidney and adrenal morphology in pregnant rats, emphasizing the need for strategies to reduce environmental pollutant exposure during critical developmental periods to protect maternal-fetal health.
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    BATF is involved in the malignant phenotype and epithelial-mesenchymal transition of colon cancer cells via ERK/PD-L1 signaling
    (Universidad de Murcia, Departamento de Biologia Celular e Histiologia, 2025) Chen, Xiaoqiong; Dong, Huaqian; Jin, Liping
    Objective. Transcription factors have emerged as primary regulators in colon cancer. Basic Leucine Zipper Transcription Factor (BATF) was found to be differentially expressed in colon cancer. This study aimed to explore the impact of BATF on the malignant phenotype and epithelial-mesenchymal transition (EMT) process. Methods. Based on The Cancer Genome Atlas (TCGA) data, the correlation between BATF and patients’ overall prognosis was analyzed. BATF expression in epithelial and colon cancer cells was evaluated. By knocking down its levels in colon cancer cells, its effects on the malignant phenotype, apoptosis, EMT progression, and ERK/PD-L1 were evaluated. Cells were treated with ERK/PD-L1 agonists, and the BATF cell regulation was re-examined. Results. BATF levels were negatively correlated with patients’ overall survival. BATF is upregulated in colon cancer cell lines, and BATF knockdown in HCT116 cells suppressed the malignant cellular phenotypes (proliferation, migration, and invasion) and increased apoptosis. BATF knockdown inhibited EMT and ERK/PD-L1 signaling activation, whereas upon agonist treatment, BATF potency was disrupted. Conclusion. This study revealed that BATF is involved in the malignant phenotype and EMT of colon cancer cells, and this process may be mediated by ERK/PD-L1 signaling
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    E2F1-induced upregulation of TROAP contributes to endometrial cancer progression
    (Universidad de Murcia, Departamento de Biologia Celular e Histiologia, 2025) Wang, Shanshan; Sun, Yidan; Guo, Minjing; Zhu, Ping; Xin, Beibei
    Purpose. To investigate the role of Trophinin-associated protein (TROAP) in endometrial cancer (EC) progression and elucidate how the transcription factor E2F transcription factor 1 (E2F1) modulates EC by upregulating TROAP expression. Methods. TROAP expression in EC tissues and cell lines was analyzed using bioinformatics databases, quantitative real-time polymerase chain reaction (qRT-PCR), western blot, and immunohistochemistry. TROAP was knocked down in EC cells to assess its effects on proliferation, migration, invasion, and glycolysis. Potential transcription factors regulating TROAP were identified, and the relationship between E2F1 and TROAP gene regulation was examined using dual luciferase assay. In vivo tumor growth was evaluated using a mouse xenograft model. Results. TROAP was overexpressed in EC tissues and cell lines compared with normal controls. High TROAP expression correlated with poor differentiation, advanced stage, lymph node metastasis, and worse overall survival in EC patients. Knockdown of TROAP inhibited the proliferation, migration, invasion, and glycolytic capacity of EC cells. E2F1 was identified as a transcriptional activator of TROAP. E2F1 over-expression enhanced TROAP expression and promoted EC cell proliferation, migration, and glycolysis in a TROAP-dependent manner. TROAP knockdown suppressed tumor growth in vivo. Conclusion. TROAP is transcriptionally activated by E2F1 and promotes EC progression by enhancing cell proliferation, metastasis, and glycolysis. The E2F1-TROAP axis may serve as a potential therapeutic target for EC treatment.
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    Aerobic exercise remodels gut microbiota to alleviate cerebral ischemia-reperfusion injury
    (Universidad de Murcia, Departamento de Biologia Celular e Histiologia, 2025) Zhu, Mingjin; Zhu, Jiajie; Pan, Jiafei; Fu, Rui; Pan, Guoyuan; Zhang, Jie
    Aerobic exercise exhibits a neuroprotective role against cerebral ischemia-reperfusion (I/R) injury, and the present study explored the underlying mechanisms. Adult Sprague-Dawley rats (n=87) were used in the study, and cerebral I/R injury in rats was modeled using middle cerebral artery occlusion and reperfusion (MCAOR), followed by interval aerobic exercise training at a moderate intensity. Colonization with gut microbiota from the trained rats was performed on MCAOR rats. Neurobehavioral assessments were performed. Cerebral infarction and neuronal damage were detected by tissue staining and molecular experiments. Gut microbiota composition was analyzed by 16S rRNA gene sequencing. Neuroinflammation was detected using an enzyme-linked immunosorbent assay. Aerobic exercise ameliorated neurological deficit, spontaneous locomotor activity, and spatial learning and memory impairment in MCAOR rats (p<0.001). Further, aerobic exercise decreased infarct volume, attenuated neuronal damage, increased SYN1 and PSD95 expression, as well as reduced neuroinflammation by upregulating IL-10 and downregulating IL-6, TNF-α, IL-17, and TGF-β in MCAOR rats (p<0.05). Aerobic exercise altered gut microbiota composition in MCAOR rats. Gut microbiota colonization in rats alleviated cerebral I/R injury by reducing neurological deficit scores, promoting spontaneous locomotor activity, decreasing infarct volume, elevating SYN1 and PSD95 expression, and improving neuroinflammation (p<0.05). In conclusion, aerobic exercise remodeled the gut microbiota in rats to attenuate cognitive dysfunction and neuroinflammation after cerebral I/R.
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    Clinicopathological diagnosis of axillary signet-ring cell-like/histiocytoid carcinoma: A case report and literature review
    (Universidad de Murcia, Departamento de Biologia Celular e Histiologia, 2025) Zhang, Ling; Li, Li; Wang, Yun; Wang, Xiao ling
    Objective. To explore the clinicopathological and morphological characteristics, diagnosis, differential diagnosis, treatment, and prognosis of primary signet-ring cell/histiocytoid carcinoma (SRCHC) of the axilla. Methods. The clinical manifestations, patho-morphological characteristics, and immunohistochemical staining results of a case of primary SRCHC in the axilla were retrospectively analyzed, and the relevant literature was reviewed. Results. The patient was a 69-year-old male. Subcutaneous gray-white nodules with unclear boundaries were visible. Microscopic examination: The tumor was located in the dermis and subcutaneous tissue. The tumor cells were arranged in a cord-like, soldier-like, or nest-like shape, with mild to moderate atypia. Some cells had obvious nucleoli. The tumor cytoplasm was eosinophilic, and mucoid material inside and outside the cells could be seen, showing a signet-ring-like or histiocytoid appearance. Immunohisto-chemical staining was positive for GCDFP-15, CK7, E-cadherin, AR, P120, GATA3 and negative for Villin, S-100, CK20, SMA, P63, CD68, TTF-1, NapsinA, ER, PR, and Ki-67 proliferation index (8%), HER2(2+) and FISH(-). The special staining AB-PAS (AB+,PAS-). Conclusion. Cutaneous axillary primary SRCHC is extremely rare and highly invasive and needs to be differentiated from a variety of metastatic tumors (breast, digestive system, lung, etc.).
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    STAT3/p-STAT3 expression is correlated with clinicopathological characteristics and prognosis in non-small cell lung cancer
    (Universidad de Murcia, Departamento de Biologia Celular e Histiologia, 2025) Li, Jili; Zhu, Yingying; Peng, Jianyue; Yang, Lan; Zhang, Li; Li, Lei
    Signal transducer and activator of transcription factor 3 (STAT3)/phosphorylated STAT3 (p-STAT) play a critical role in tumorigenesis, however, there is limited information on its prognostic value in non-small cell lung cancer (NSCLC). To address this question, 239 lung cancer and 71 normal lung tissue samples were obtained in this study. Immunohisto-chemistry was applied to detect STAT3/p-STAT3 expression. Pearson’s Chi-squared test and the Kaplan-Meier method were conducted to evaluate associations with patients’ clinical characteristics and survival. According to our results, STAT3/p-STAT3 was significantly upregulated in lung cancer tissue (p<0.001). Moreover, p-STAT3 expression was significantly correlated with age (p=0.046) and pathological types (p=0.037). In survival analysis, STAT3 positivity was negatively associated with survival in patients older than 60 years (p=0.043) but failed to be an independent prognostic factor in multivariate analysis (p=0.083). Therefore, STAT3/p-STAT3 may serve as a critical biomarker in NSCLC
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    Assessing the expression of Nectin-4 in solid tumors by immunohistochemistry – what do we know?
    (Universidad de Murcia, Departamento de Biologia Celular e Histiologia, 2025) Sanders, Christine; Kristiansen, Glen
    Antibody-Drug Conjugates (ADCs) represent a promising class of anti-cancer substances that combine the specificity of monoclonal antibodies with the potency of cytotoxic drugs, hence they enable a new approach of targeted therapy. The use of the ADC Entfortumab Vedotin (EV), which targets the viral receptor Nectin-4, showed an impressive clinical response in metastatic urothelial carcinoma. In this review, we present what is known about the expression of Nectin-4 in various tumor entities, focusing on immunohistochemistry as a diagnostic venue to detect positive expression, as this inexpensive technique is readily available in pathology laboratories. Various studies demonstrated expression of Nectin-4 in many solid tumor entities with the highest expression rates in urothelial carcinomas and breast cancer. To date, the relevance of the subcellular compartment of immunoreactivity (membranous vs. cytoplasmic) is still unclear in respect of its predictive value for EV therapy, which ought to be clarified in further studies.
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    Time course analysis of changes in neuronal loss, oxidative stress, and excitotoxicity in gerbil hippocampus following ischemia and reperfusion under hyperthermic conditions
    (Universidad de Murcia, Departamento de Biologia Celular e Histiologia, 2025) Lee, Tae Kyeong; Kim, Dae Won; Park, Joon Ha; Lee, Choong Hyun; Yang, Se Ran; Shin, Myoung Cheol; Won, Moo Ho; Cho, Jun Hwi; Ahn, Ji Hyeon
    Oxidative stress and excitotoxicity are the major causes of neuronal death/loss in the brain following ischemia and reperfusion (IR). Hyperthermia is known to exacerbate ischemic neuronal damage; however, the underlying mechanisms remain unclear. This study investigated the mechanisms underlying neuronal damage caused by IR injury (IRI) under hyperthermic conditions in the gerbil hippocampal CA1 region. Gerbils were controlled at normothermia (37.5±0.2°C) or hyperthermia (39.5±0.2°C). After temperature control for 30 min, the animals received IRI (following 5 min of transient forebrain ischemia) or sham ischemia, and were subsequently sacrificed at 0, 3, 6, 12, 24, 48, and 120h after IRI. Neuronal death was examined using neuronal nuclear antigen immuno-histochemistry and Fluoro-Jade B histofluorescence. Oxidative stress was analyzed by immunohistochemistry for 8-Hydroxy-2'-deoxyguanosine (8OHdG) and superoxide dismutase 2 (SOD2). Excitotoxicity was investigated by immunohistochemistry and western blotting for glutamate transporter 1 (GLT1). Immuno-histochemical staining for glial fibrillary acidic proteins (GFAP) was performed to detect reactive astrogliosis. Loss of pyramidal neurons was detected earlier (48h post-IRI) in the hyperthermia-IRI group than in the normothermia-IRI group (120h post-IRI). Further, 8OHdG and SOD2 immunoreactivity in the hyper-thermia-IRI group was significantly higher than that in the normothermia-IRI group. Changes in GLT1 immunoreactivity in both groups were biphasic, indicating that the immunoreactivity and protein levels were significantly lower in the hyperthermia-IRI group. GFAP immunoreactivity was enhanced following neuronal loss, indicating that the immunoreactivity was significantly higher in the hyperthermia-IRI group. Taken together, these results suggest that brain IR under hyperthermic conditions can aggravate neuronal damage in the hippocampal CA1 region through severe oxidative stress and excitotoxicity