AIMS:Anaplastic lymphoma kinase (ALK) rearrangements are actionable drivers in non-small cell lung carcinoma (NSCLC), but the biological significance of ALK-immunohistochemistry (IHC) positivity in high-grade pulmonary neuroendocrine carcinoma (NEC) remains unclear. This study evaluated the diagnostic and therapeutic implications of discordant ALK IHC and genomic findings and the role of multimodal molecular testing in resolving them. METHODS:We retrospectively analysed eight South Asian patients (Indian and Nepali) with de novo high-grade pulmonary NEC and diffuse ALK immunoreactivity treated at a tertiary cancer centre in India. Comprehensive molecular profiling using DNA- and RNA-based next-generation sequencing (NGS) and ALK fluorescence in situ hybridisation (where tissue was adequate) was performed. Clinical outcomes and responses to ALK-targeted tyrosine kinase inhibitors (TKIs) were assessed. RESULTS:ALK IHC positivity was observed in 8 of 100 selectively tested cases among 319 high-grade pulmonary NECs diagnosed between 2019 and 2025. The cohort included seven SCLCs (one combined adenocarcinoma-SCLC) and one large-cell neuroendocrine carcinoma (LCNEC). Median age was 51 years; 75% were female and 87.5% never-smokers. Among five comprehensively profiled cases, true ALK rearrangements were confirmed in two (one LCNEC and one SCLC), both detectable only by RNA sequencing. Durable benefit from ALK-TKI therapy was seen only in the molecularly confirmed LCNEC case (>16 months), whereas ALK IHC-positive but NGS-negative cases progressed rapidly. CONCLUSIONS:True ALK rearrangements in high-grade pulmonary NEC are rare but highly actionable. ALK IHC alone is an unreliable predictor of therapeutic benefit. RNA-based sequencing is essential for fusion detection. Comprehensive molecular confirmation, with RNA sequencing as the preferred modality, should precede any initiation of ALK-targeted therapy in high-grade pulmonary NEC.
Aims Pathology is undergoing a paradigm shift as diagnostics become increasingly multimodal and computational. Yet legacy structures, incentives and workflows have not yet evolved. This misalignment created systemic vulnerabilities that threaten diagnostic precision and the profession’s future. Here, we establish a framework for the cognitive integration of rapidly evolving diagnostic innovations in pathology. Methods To characterise critical inflection points and opportunities for conceptual transformation we mapped seven diagnostic scenarios: programmed death ligand 1 testing, next-generation sequencing reimbursement constraints, artificial intelligence-based triaging, integrated diagnostics, germline (pharmacogenomics) testing, trial design and emerging assurance frameworks outside traditional pathology. Our synthesis draws from peer-reviewed literature, policy analysis, institutional data, and qualitative insights to highlight where pathologists can elevate their role as integrator of clinical, morphological and molecular knowledge. Results Across the seven scenarios, common patterns emerged: unintentional consequences of well-intended initiatives, commoditisation, unsustainable economic models, underleveraged efficiency gains, misaligned infrastructure, missed clinical opportunity, regulatory rigidity and erosion of diagnostic accountability. These patterns signal not only operational gaps but a cognitive crisis. A failure by pathologists to position themselves as more than an interpretative service. Pathologists must assume the role of diagnostic architects, synthesising multimodal data into structured, clinically actionable insights and engaging more directly with physicians, those organising clinical trials and patients as partners in precision medicine. Conclusions The emerging competencies of diagnostic synthesis, systems thinking, digital fluency, and strategic presence in value-based care offer a mindset guide for both personal growth and anchoring the discipline’s next transformational step to improve patient care.
AIMS:To characterise gene expression differences between oral cavity squamous cell carcinoma (OSCC) and non-neoplastic oral mucosa using targeted transcriptome profiling and to evaluate gene expression patterns associated with tumour differentiation. METHODS:Formalin-fixed, paraffin-embedded tissue from 16 resected OSCCs (3 well differentiated, 9 moderately differentiated and 4 poorly differentiated) and 7 non-neoplastic oral mucosa samples was analysed. RNA was isolated from microdissected tissue and profiled using a targeted next-generation sequencing assay. Differential gene expression and pathway enrichment analyses were performed, including comparisons across histologic grades. RESULTS:OSCC demonstrated broad transcriptomic differences compared with non-neoplastic oral mucosa, with enrichment of pathways related to extracellular matrix remodelling, cell adhesion, immune regulation, oncogenic signalling and cellular metabolism. Grade-stratified analyses identified additional differences involving epithelial differentiation, immune response, lipid metabolism and oxidative phosphorylation pathways. CONCLUSIONS:OSCC exhibits broad transcriptomic dysregulation involving extracellular matrix remodelling, cell adhesion, immune signalling, oncogenic signalling and cellular metabolism. Grade-stratified findings demonstrate molecular differences associated with tumour differentiation but require validation in larger independent cohorts. These findings may inform future studies of biomarkers and biologically relevant pathways in OSCC.
AIMS:Specific to normal gastric epithelium, Claudin 18.2 (CLDN18.2) is a tight junction protein. CLDN18.2 immunohistochemistry is a companion diagnostic used to identify oesophageal and gastric adenocarcinoma patients eligible for targeted therapy with zolbetuximab. It has demonstrated survival benefits in advanced upper gastrointestinal (UGI) cancers, with many studies now exploring its potential use beyond the UGI tract. This study aimed to examine CLDN18.2 expression in a peritoneal malignancy patient cohort. METHODS:CLDN18.2 immunohistochemistry was performed on archived tissue from patients who underwent cytoreductive surgery at a national centre for peritoneal malignancy. CLDN18.2 immunoprofiles were compared in two key tumour cohorts: peritoneal metastases from colorectal adenocarcinoma and appendiceal mucinous neoplasms. Positivity was defined as moderate-to-strong membranous staining in >75% of tumour cells. In addition, any CLDN18.2 positivity in tumour cells (>0% of cells showing moderate-to-strong membranous staining) was recorded in all cases. RESULTS:64 cases were examined; primary tumour sites of origin were colorectal (n=34, 53%) and appendiceal (n=30, 47%). CLDN18.2 positivity in the overall appendiceal group was 17% compared with 3% in colorectal adenocarcinomas (p=0.090). In the appendiceal group, CLDN18.2 positivity was only demonstrated in high-grade appendiceal mucinous carcinomas (22%, 5 of 23). CLDN18.2 positive staining (>0% of tumour cells) was significantly increased in the appendiceal group compared with colorectal adenocarcinoma (53% vs 3%, respectively) (p<0.0001). CONCLUSIONS:These results demonstrate CLDN18.2 expression in a subset of appendiceal peritoneal metastases. This is one of the first focused studies showing CLDN18.2 expression in this tumour group, perhaps highlighting a future role for targeted therapies in those with limited curative oncological options.
Artificial intelligence (AI) has emerged as a promising adjunct in surgical pathology, particularly in the diagnosis of prostate cancer, where variability in interpretation or missed cancer foci can significantly affect patient management. This review provides a concise, practice-oriented overview of the two Food and Drug Administration (FDA)-cleared AI tools for prostate biopsy interpretation: Paige Prostate Detect and Ibex Prostate Detect (formerly Galen Second Read). We examine their regulatory indications, diagnostic performance and integration requirements within digital pathology workflows. Emphasis is placed on real-world implementation considerations, including variation in technical inputs and the level at which data are analysed. We highlight less obvious risks, such as domain shift and the potential for inequitable performance in under-represented patient populations. Trade-offs between sensitivity and specificity, particularly in the context of AI-assisted pathologist assessments, are discussed using data from clinical validation studies. We also consider the variable impact of AI tools depending on the user's expertise, noting enhanced diagnostic consistency for general pathologists. By highlighting both the opportunities and limitations of integrating AI into routine practice, we aim to provide pathologists with a pragmatic understanding of how these systems may influence diagnostic workflows and to emphasise that FDA clearance must be complemented by local validation as well as ongoing performance monitoring to ensure safe and equitable deployment.
AIMS:High-grade extremity soft tissue sarcomas (eSTS) are rare, heterogeneous malignancies with a high metastatic potential. Prognostic assessment remains challenging due to wide variation in outcomes. Current risk stratification relies on traditional risk factors like age, histology, grade and tumour size, which are embedded in risk classification scores. Recent advances in the fields of biochemistry, pathology and molecular genetics may offer additional prognostic insights, although their clinical utility remains unclear. This scoping review aimed to map the evidence on clinically available biomarkers with potential prognostic value in adults with high-grade eSTS. METHODS:A broad search of MEDLINE and Embase identified 9739 records, of which 74 studies met the eligibility criteria. RESULTS:Overall, available evidence is retrospective and heterogeneous. Potential biomarkers were identified across three domains: biochemical, pathological and molecular. Although several biomarkers showed potential prognostic value, few studies assessed their independence from key confounders. CONCLUSIONS:Standardised validation, with adjustment for established prognostic variables, is needed before these biomarkers can be integrated into risk prediction models for routine clinical practice.
B cell acute lymphoblastic leukaemia (B-ALL) infrequently presents with undetectable or very low peripheral blood (PB) lymphoblasts, which may cause diagnostic difficulties. We report the clinicopathological features of paediatric patients with B-ALL who presented with low (<5%; n=31) PB lymphoblasts by flow cytometry. 15 patients presented with <1% PB lymphoblasts (range: 0.0%-0.9%), a level potentially undetectable by manual smear review and standard 100-cell count. Compared with patients presenting with ≥5% PB lymphoblasts (n=45), those with <5% had more frequent musculoskeletal symptoms, less frequent lymphadenopathy and hepatosplenomegaly, higher platelet counts, lower white blood cell counts and lower lactate dehydrogenase. The presence of low PB lymphoblasts was associated with favourable cytogenetics (ETV6::RUNX1 or high hyperdiploidy without IKZF1 deletion) and less frequent central nervous system involvement. Aleukemic/low PB lymphoblast presentation of B-ALL is associated with unique clinicopathological features that overlap with non-malignant disorders. A high degree of clinical suspicion and careful review of PB flow cytometry data are required for timely diagnosis.
AIMS:This research was designed to establish an innovative diagnostic strategy employing whole-slide imaging (WSI) technology to address the diagnostic difficulties arising from the intricate histological architecture and morphological diversity observed in oral squamous cell carcinoma (OSCC). The developed methodology enables precise early identification and histomorphology-driven prognostic stratification of malignant lesions, thereby improving clinical management and patient prognosis. METHODS:We propose a multi-task learning framework that combines local-global attention mechanisms with adaptive decision fusion (MILGDF). This model utilises instance-level category-specific attention to enhance feature extraction efficacy while overcoming the limitations inherent in traditional bag-level attention methods. An adaptive weighting system was incorporated to dynamically adjust the contribution of local and global features, ensuring optimal performance in dual tasks of OSCC diagnosis and prognostic stratification. RESULTS:Rigorous validation on the HIDOC and TCGA-OSCC datasets revealed the predictive performance of our model. The MILGDF framework attained an area under the curve of 0.952 (accuracy: 0.909) on HIDOC and 0.745 (accuracy: 0.725) on TCGA-OSCC. Statistical comparison using DeLong's test and paired t-tests demonstrated significantly superior performance (p<0.05) over existing comparative models in both diagnostic classification and prognostic stratification. CONCLUSIONS:Our findings demonstrate that the MILGDF model represents an improvement in whole-slide image-based OSCC analysis, delivering enhanced diagnostic accuracy and prognostic reliability relative to current approaches. The framework's consistent performance highlights its computational benchmark value and preliminary translational potential for early OSCC detection and auxiliary treatment planning, serving as a valuable asset for prognostic evaluation and therapeutic strategy formulation.
AIMS:MRI-targeted needle core biopsy (MRI-NCB) improves detection of clinically significant prostate cancer (csPCa), but whether it can replace systematic ultrasound-guided biopsy (US-NCB) remains debated, as most studies have focused on cancer detection and grade. METHODS:We retrospectively analysed 562 patients with PI-RADS 3-5 lesions who underwent both MRI-NCB and concurrent US-NCB. Outcomes included cancer detection, Grade Group (GG) and adverse features (cribriform morphology and intraductal carcinoma (IDCP)). csPCa was defined as GG ≥2. A composite endpoint of clinically meaningful under-detection or underestimation was defined as missed or under-graded csPCa and/or missed adverse histological features on MRI-NCB relative to US-NCB. RESULTS:MRI-NCB alone would have missed PCa in 13.0% (73/562) of patients, including csPCa in 11.4% (64/562) and would have underestimated GG in 13.3% (75/562). Systematic biopsy identified additional cribriform morphology in 4.3% (24/562) and IDCP in 2.5% (14/562) of patients not detected on MRI-NCB. Overall, MRI-NCB alone would have resulted in clinically meaningful under-detection or underestimation in 16.4% (92/562). Of these, 63.0% had missed or under-graded csPCa only, 30.4% had missed adverse histologic features only and 6.5% had both. Missed cancers were more frequent in lower PI-RADS lesions whereas upgrading was more common in higher PI-RADS lesions. Incremental detection of IDCP was significantly higher in PI-RADS 5 compared with PI-RADS 4 lesions (adjusted p=0.048). CONCLUSIONS:MRI-targeted biopsy alone may incompletely assess cancer detection and tumour biology. Systematic biopsy provides complementary diagnostic value, and omission may result in clinically meaningful under-detection or underestimation, even in high PI-RADS lesions.
Aims Accurate distinction of inflammatory bowel disease (IBD) and gastrointestinal tuberculosis (GITB) on mucosal biopsies remains challenging, especially in South-East Asia. Our previous meta-analysis highlighted that mucosal basal plasmacytosis (BP) can help in identifying IBD although evidence is limited. This study was planned to evaluate the utility of mucosal BP and combined presence of BP and mucosal eosinophilia (ME) (BP+ME) in differentiating ulcerative colitis (UC), Crohn’s disease (CD) and GITB using endoscopic mucosal biopsies. Methods We retrospectively analysed 500 mucosal biopsies from patients diagnosed with UC, CD and GITB based on clinical, radiological, endoscopic findings and treatment response. Inclusion and exclusion criteria were applied, and histological evaluation was performed independently by two experienced pathologists. Presence of BP and BP+ME was systematically compared across patient groups. Results Of the 500 biopsies reviewed, 412 met inclusion criteria (UC: 194, CD: 68, GITB: 114, IBD-unclassified: 36). BP was significantly more prevalent in both UC and CD than in GITB. BP+ME was significantly more prevalent in mucosal biopsies from IBD than in GITB. Also, in segmental mucosal biopsies from IBD patients, BP was found significantly more in three or more biopsy fragments than in biopsies from GITB. Both BP and BP+ME demonstrated good diagnostic utility in differentiating IBD from GITB and CD from GITB (positive likelihood ratio 3.24 and 4.35, respectively). Conclusions Histological identification of mucosal BP and/or BP+ME provides moderate diagnostic utility in distinguishing IBD from GITB. Identification of BP in three or more biopsy fragments further strengthens histological diagnosis of IBD.
In clinical practice, thyroid function tests (TFTs) usually comprise thyroid-stimulating hormone (TSH) and free thyroxine (FT4), with free triiodothyronine (FT3) measured less frequently. We report a 76-year-old woman with autoimmune thyroiditis presenting with raised TSH and incongruously elevated FT4. The discordance between biochemical findings and clinical status prompted further investigations for assay interference. TFTs were assessed using four different immunoassay platforms and equilibrium dialysis. Additional studies included heterophilic antibody blocking and polyethylene glycol (PEG) precipitation. PEG precipitation demonstrated a high-molecular-weight interferent, consistent with thyroid hormone autoantibodies. FT4 measured by two-step immunoassays (Abbott Alinity and Beckman DxI) aligned with FT4 reported by equilibrium dialysis, whereas one-step assays (Roche Cobas and Siemens Atellica) reported spuriously elevated FT4. One-step immunoassays are particularly susceptible to interference from thyroid hormone autoantibodies, which may yield misleading results. Recognition of potential TFT assay interference and the use of alternative methodologies are essential for accurate diagnosis and appropriate patient management.
AIMS:Granulomatous lobular mastitis (GLM) is a rare, chronic, benign inflammatory disease of the breast with an unclear aetiology. This study aimed to characterise the microbial features of GLM using metagenomic next-generation sequencing (mNGS) and to provide potentially relevant microbial clues for clinical evaluation. METHODS:Twenty fresh lesion tissue samples were collected from 15 female patients with GLM, including one representative sample per patient and five additional deep tissue samples. Clinical data collection, mNGS, bioinformatics analysis and data interpretation were performed to characterise the microbial profiles of GLM lesions. RESULTS:In this study, all patients presented with palpable breast masses, breast pain and abscess formation. More than half showed increased white blood cell counts, neutrophil percentages, C reactive protein levels and erythrocyte sedimentation rates together with decreased lymphocyte percentages. Based on genus-level filtering, mNGS identified 16 bacterial genera, 14 fungal genera and 3 viral genera, revealing a complex but bacteria-dominated microbial profile. The most frequently detected bacterial genera were Corynebacterium, Cutibacterium, Acinetobacter, Staphylococcus and Hathewaya, with marked interpatient variation in relative abundance, while fungal profiles were relatively more concentrated. In five patients with both superficial and deep tissue samples, microbial profiles differed across sampling depths, particularly for bacterial composition. CONCLUSIONS:mNGS revealed a complex, bacteria-dominated microbial profile in GLM lesions and indicated that sampling depth may influence the detected microbial profiles. These findings may provide useful clues for clinical evaluation, but the pathogenic significance of these micro-organisms remains to be elucidated.
Triple-negative breast cancer (TNBC) is defined in routine practice by the absence of oestrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2) expression using fixed immunohistochemical and in situ hybridisation cut-offs. Although this framework ensures reproducibility and regulatory consistency, it does not equate to biological uniformity. TNBC is an operational clinicopathological category defined by reproducible biomarker thresholds applied to continuous gradients of receptor expression. This review examines the evolution of hormone receptor assessment from semiquantitative composite scoring systems to the current ≥1% ER positivity threshold, and analyses the diagnostic and clinical implications of ER-low-positive (1%-10%) tumours. We discuss the rarity and interpretative challenges of ER-/PR+ phenotypes, the impact of evolving HER2 testing criteria, including borderline amplification and HER2-low categories, and the consequences of guideline variation on TNBC classification. We also address histological heterogeneity within TNBC and propose a pragmatic three-tier framework that distinguishes definite TNBC, context-dependent/borderline TNBC and non-TNBC categories. Collectively, these considerations highlight that TNBC is a regulatory definition anchored to diagnostic thresholds rather than a discrete molecular entity. Awareness of definitional sensitivity at receptor cut-off margins is essential for accurate reporting, avoidance of misclassification and informed multidisciplinary decision-making. Recognition of TNBC as a biologically heterogeneous spectrum has implications for therapeutic selection, trial eligibility and future refinement of classification systems.
Transdifferentiation from follicular lymphoma (FL) to histiocytic/dendritic cell sarcoma (HDS) is rare and requires molecular confirmation of shared clonal origin. Targetable mutations such as BRAF V600E may offer therapeutic opportunities in such aggressive neoplasms. We report an exceptional case of untreated localised FL transdifferentiated to an HDS after 18 years. Shared BCL2 rearrangement and mutation profile confirmed a clonal link, while the HDS acquired an additional BRAF V600E mutation. Treatment with BRAF/MEK inhibitors yielded a sustained 18-month clinical response. The disease later relapsed as high-grade B-cell lymphoma with MYC and BCL2 rearrangements (HGBCL-MYC/BCL2), still harbouring the BRAF mutation. Complete remission was achieved with Rituximab, Cyclophosphamide, Hydroxydaunorubicin, Oncovin and Prednisone, but the double-hit lymphoma relapsed 14 months later.This case illustrates sequential transformation from FL to BRAF-mutated HDS with excellent response to BRAF/MEK inhibition, followed by evolution into HGBCL-MYC/BCL2 responding transiently to immunochemotherapy, emphasising the value of repeated histological and molecular reassessment in FL evolution.
AIM:The traditional three-level H&E sectioning protocol for prostate biopsies was developed for ultrasound-guided systematic sampling and predates lesion-targeted biopsy approaches. Multiparametrical MRI (mpMRI) has improved detection of clinically significant prostate carcinoma but has also increased biopsy volume, workload, costs and digital pathology requirements, including whole-slide imaging and artificial intelligence (AI) integration. METHODS AND RESULTS:A retrospective institutional cost-yield analysis was performed on prostate biopsy cases at Beth Israel Deaconess Medical Center (2015-2022), comparing systematic 12-core biopsies with combined systematic and mpMRI-targeted biopsies. Case volume, tissue blocks and H&E slides were analysed. Per-slide costs were calculated, and additional digital pathology and AI workflow costs were estimated using published data and vendor pricing. Case volume increased by 27% over 7 years, while combined systematic and mpMRI-targeted protocols increased tissue blocks and H&E slides by 39%. The cost per H&E slide was $7.18, with digital pathology and AI workflows adding an estimated $4.30-5.00 per slide. In systematic 12-core biopsies, third-level sectioning identified four additional low-volume carcinomas at a cost of $2283 per diagnosis. In combined biopsies, two additional carcinomas were detected exclusively on the third level, both Grade Group 1, with a cost of $27 657 per diagnosis. CONCLUSION:Routine three-level H&E sectioning in combined systematic and mpMRI-targeted prostate biopsies demonstrated low incremental diagnostic yield and substantial additional processing cost. A two-level protocol with selective third-level sectioning may preserve detection of clinically significant carcinomas in this institutional cohort, while reducing workload and cost in the digital pathology era.
Objective While kinase-altered spindle cell tumours were classically recognised in paediatric superficial soft tissues, recent literature indicates an expanding clinicopathologic spectrum. This study investigates a cohort of RAF/BRAF-altered mesenchymal tumours to further characterise their presentations in adults, deep-seated/visceral locations, variable immunophenotypes and complex molecular evolution.Methods Eight molecularly confirmed RAF/BRAF-altered mesenchymal tumours were retrospectively evaluated. Clinical characteristics, histomorphology, immunohistochemistry, targeted next-generation sequencing profiles and follow-up data were comprehensively analysed.Results The cohort comprised seven females and one male (median age, 34.5 years). Tumours arose in soft tissues (n=5, including the deep pelvis) and visceral organs (n=3; two breast, one lung). Histologically, the neoplasms exhibited a broad morphologic spectrum: three demonstrated low-grade spindle cell morphology, whereas five displayed high-grade pleomorphic or fibrosarcoma-like features, including one pelvic tumour mimicking myxoid leiomyosarcoma. Immunophenotypes diverged significantly with histologic grade: low-grade tumours retained CD34 and S100 coexpression, whereas high-grade lesions consistently lost both markers, with one case exhibiting focal Desmin positivity. Molecular profiling revealed ubiquitous mitogen-activated protein kinase pathway activation, identifying six kinase gene fusions (including novel IQSEC1::RAF1 and PLEKHH3::BRAF variants) and two BRAF V600E mutations. High-grade tumours frequently harboured concurrent tumour suppressor gene alterations (eg, TP53, PTEN). Notably, one pelvic tumour exhibited a trunk NTRK1 mutation alongside a subclonal BRAF V600E mutation. Notably, despite the alarming high-grade histomorphology in several cases, clinical behaviour remained relatively indolent, with no disease-related deaths to date.Conclusions RAF/BRAF-driven mesenchymal tumours possess a broader clinicopathologic spectrum than traditionally recognised, frequently affecting adults and deep/visceral sites. Their inherently variable immunophenotypes and the presence of high-grade morphologic features do not strictly predict an aggressive clinical trajectory. Comprehensive molecular profiling is essential to refine diagnostic criteria, accurately identify these neoplasms, and elucidate the genomic events associated with tumour progression.
Diagnosing low-grade intraductal epithelial proliferations and distinguishing hyperplasia from neoplasia has traditionally relied on well-established morphological and immunophenotypic criteria. However, in routine practice, differentiating luminal epithelial proliferations that are not necessarily clonal from bona fide neoplastic precursor lesions remains challenging. In specific clinical scenarios, such as gynaecomastia, adolescent breast tissue and fibroepithelial lesions, epithelial proliferations may appear morphologically and immunophenotypically worrisome for neoplasia, yet the clinical context supports a non-neoplastic process. Rather than representing conventional clonal neoplasia, these changes may reflect hormonally driven or stromal-induced luminal differentiation and often lack the sharp demarcation typical of conventional neoplasia. This narrative review delineates these context-dependent diagnostic pitfalls and proposes an integrated framework that emphasises architectural features, clonal demarcation and the clinical setting. By positioning these borderline lesions within a biological continuum and refining diagnostic thresholds in context, this approach aims to improve diagnostic reproducibility, mitigate the risk of overdiagnosis and support appropriate, risk-adapted patient management.
In Africa, chronic liver conditions are discordantly higher due to infectious and parasitic aetiologies, especially viral hepatitis. Early diagnosis is a linchpin for successful management and improved outcomes; however, diagnostic power is extremely limited. Yet, profound gaps compromise every step of the diagnostic continuum. Histopathological evaluation through liver biopsy remains the gold standard for establishing aetiology, grading inflammation and staging fibrosis. Biopsy services in Africa are limited by limited infrastructure, a deficit of qualified professionals, substantial costs, unreliable tissue samples and limited access to advanced pathology techniques such as immunohistochemistry and molecular testing. Non-invasive diagnostic tools such as serum markers, transient elastography and imaging techniques are unequally accessible, poorly updated for African-specific aetiologies and largely inaccessible outside tertiary centres. This review explores the aetiological spectrum of chronic liver disease in Africa and evaluates the availability and performance of both histological and non-invasive diagnostic techniques. This review illustrates gaps affecting screening, staging, initiation of management and hepatocellular carcinoma surveillance. Addressing these diagnostic limitations through improved infrastructure, expanded professional training and local validation of non-invasive tools is essential to reducing the burden of liver disease across Africa. In addition, it offers tiered and feasible recommendations while considering the current reality of healthcare in sub-Saharan Africa.
