Cytology at the crossroads: Safeguarding equity in the molecular era

Dear Editor,

Molecular pathology has transformed the way we classify, diagnose, and treat human disease. However, progress carries a paradox: The advances that promise precision may also deepen inequity. Access to next-generation sequencing (NGS) and companion diagnostics remains profoundly uneven across regions and institutions. In this landscape, cytology, a discipline built on accessibility, minimal invasiveness, and cost-effectiveness, stands at a pivotal crossroads. Will it remain the most inclusive diagnostic platform, or will increasing molecular dependency erode the equity that has long defined it?

Modern cytology has evolved far beyond morphology alone. Fine-needle aspirations and liquid-based preparations now routinely support immunocytochemistry, fluorescence in situ hybridization, polymerase chain reaction-based techniques, and even NGS. Several studies have confirmed that cytologic material, including cell blocks, smears, and residual fluids, provides deoxyribonucleic acid (DNA) and ribonucleic acid of sufficient quality for molecular profiling.^[1-3] Because it is less invasive, repeatable, and widely available, cytology has become an enabler of precision medicine. It bridges the gap between sophisticated molecular testing and practical patient care, particularly where surgical biopsies are not feasible. Rather than being a “second-class specimen,” cytology is increasingly the front line of equitable molecular pathology. It represents a diagnostic approach that makes precision medicine possible, not exclusive.

Across organ systems, the International Academy of Cytology, International Agency for Research on Cancer, and World Health Organization Cytopathology Reporting Systems for lung, pancreaticobiliary, and most recently lymph node, spleen, and thymus share a guiding philosophy: Morphology first, ancillary testing when available.^[4-6] Each framework defines standardized diagnostic categories grounded in cytomorphologic criteria, while encouraging the use of immunocytochemistry in selected cases and molecular assays when feasible, conceived as valuable adjuncts rather than mandatory steps. This pragmatic design safeguards global applicability and resource neutrality, maintaining diagnostic access even where molecular infrastructure remains limited.

The Bethesda System for Reporting Thyroid Cytopathology (2023) follows a graded model of integration: Molecular testing is recommended for indeterminate cases, particularly those in the category of atypia of undetermined significance/follicular lesion of undetermined significance (category III), to refine the risk of malignancy, but is not required across the spectrum.^[7] In cervical cytology, the Bethesda terminology remains morphological, listing human papillomavirus (HPV) results only as adjunctive information, even though population-level screening increasingly relies on HPV molecular detection. Taken together, these systems illustrate how cytology has managed to balance innovation with inclusivity, adopting molecular advances without making them a gatekeeper.

However, the pace of molecular advancement continues to accelerate. In many cancers, such as lung adenocarcinoma, colorectal carcinoma, and breast carcinoma, therapeutic eligibility now depends on identifying specific genomic alterations (for example, EGFR mutations, KRAS mutations, or HER2 amplification). In others, including hematolymphoid, salivary gland, or soft-tissue neoplasms, molecular profiling also holds significant diagnostic value. This growing molecular dependency risks creating a new form of diagnostic inequity. Global surveys, such as the International Association for the Study of Lung Cancer survey on molecular testing in lung cancer, reveal wide disparities in access to essential assays.^[8] Reports from low- and middle-income countries highlight logistical, financial, and infrastructural barriers that limit the implementation of precision diagnostics.^[9,10] Even within high-income regions, smaller institutions may lack on-site sequencing capabilities, relying on external referral networks that increase cost and delay results.

If histology’s growing reliance on molecular parameters is transferred uncritically to cytology, pathology could lose one of its most inclusive tools. Cytology’s defining strengths are accessibility, efficiency, and its ability to yield meaningful answers from minimal material. Preserving these qualities is essential. Without caution, precision may become the new inequity.

Equity and precision are not opposing forces: they can and must advance together. Practical strategies can help cytology remain inclusive while integrating molecular methods. Tiered testing can distinguish “essential” from “expanded” panels, allowing gradual implementation without marginalizing laboratories that lack full molecular capacity. Regional molecular hubs can consolidate expertise and resources, improving turnaround time and cost-efficiency. Optimized preanalytics, including rapid on-site evaluation, standardized fixation, and consistent cell-block preparation, preserves nucleic acid quality and extends the usefulness of every sample. When molecular yield is limited, circulating tumor DNA or repeat minimally invasive sampling offers feasible alternatives. Digital and artificial intelligence-assisted cytology can also help bridge geographic and expertise gaps through telecytology and automated interpretation. Building on these strategies, the idea of molecular readiness, understood as collecting, processing, and storing samples in ways that preserve the possibility of future testing, provides a practical framework for maintaining the balance between precision and equity. In this approach, access is protected because molecular testing becomes an opportunity rather than a requirement.

The expanding role of molecular tools in diagnostic pathology brings major opportunities but also new challenges. As molecular markers and large sequencing panels become more common, there may be a tendency to extend testing beyond what is clinically justified. The same principles that support molecular readiness should guide the development of future classifications. Molecular criteria should be incorporated only when they provide clear and proven benefits for diagnosis, prognosis, or patient management. Adding molecular complexity without meaningful clinical value increases cost and turnaround time and may unintentionally widen existing disparities.

As it has throughout its history, cytology can again serve as a model for equitable innovation in the molecular era. To achieve this, the discipline must safeguard its inclusivity while continuing to advance responsibly. Future classifications should continue to recognize cytology’s value as a bridge between precision and access. The lesson is simple but vital: technological sophistication must not come at the cost of universality. Precision without equity is not progress.