Adequacy in cytopathology: focus on cytology specimen use in molecular testing

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Varsha Manucha, MD
Martin J. Magers, MD
Sinchita Roy-Chowdhuri, MD, PhD
Derek B. Allison, MD
Efrain A. Ribeiro, MD, PhD

May 2023—In the first article in our series on adequacy in cytology, published in January 2023 (bit.ly/3MDNVzr), we summarized current approaches to defining adequacy for the purpose of primary diagnosis in the majority of specimen types encountered routinely in cytology practice. As we saw, while the essence of adequacy is constant across reporting systems, the technical definitions can vary significantly by specimen type. A major advantage of adopting standardized reporting systems for cytology specimens is a unification of the language that pathologists use to communicate with clinicians and classify a diagnosis accurately. In cases in which a specimen is inadequate, the diagnosis should be interpreted with caution.

While current adequacy standards have excelled at facilitating the practice of cytopathology by providing a unified language for primary diagnosis, they do not account for a more complex understanding of adequacy that is evolving rapidly in clinical practice. Namely, they fail to account for the emerging use of cytology specimens in molecular testing. In many cases, the adequacy standards used for primary diagnosis do not consider the subsequent need for molecular testing from the same specimen. In this article, we will address the hurdles that are still in the way of establishing adequacy standards for cytology specimens with a focus on molecular diagnostic testing.

Several studies have demonstrated that cytology specimens are suitable for molecular testing.^1-3 Cytology specimens are now being used for routine molecular testing, specifically for prognostic and therapeutic testing in lung cancer, and guidelines from the CAP/IASLC/AMP for the use of cytology specimens for molecular testing were published in 2018.⁴ Endobronchial ultrasound-guided fine-needle aspiration has a prominent role in establishing the diagnosis of primary lung cancers, and collecting tissue biopsies can be challenging, leaving only glass slide smears with or without a cell block. Rapid onsite evaluation (ROSE) services have greatly improved diagnostic adequacy of specimens for these cases, which has resulted in fewer re-operations and lower costs. However, as cytology specimens are increasingly used for molecular testing, onsite adequacy assessments will have to evolve to account for the collection of sufficient additional tissue for molecular testing.

According to a recent survey of health care professionals in 102 countries about molecular testing failures in lung cancer cases, the main reasons for testing failures were an insufficient amount of tumor cells (83 percent) and inadequate tissue quality (55 percent).⁵ As it stands now, these minimum standards for a specimen to be used for molecular testing, such as next-generation sequencing, can vary among molecular laboratories. Moreover, as the importance of molecular testing continues to grow, more patients are needing to be re-operated on solely to obtain additional tissue for molecular testing. As things stand with our diagnostic reporting systems today, there is a gap in the definition of adequacy between adequacy for diagnosis and adequacy for ancillary testing. This survey highlights a growing recognition that while a specimen may be considered adequate for a primary diagnosis, it does not mean that the same specimen will be adequate for the molecular testing required for prognostic and therapeutic decision-making.