Precision surgical oncology? The treasure is in the tissue

In the era of precision oncology, the molecular biological data derived from patient biospecimens directly influences patient management. For cancer resection specimens, traditional types of specimen-derived data, such as tumor type, grade, pathological stage, and resection margin status, also are essential and must be accurately reported; however, these data are derived from histopathological observation and are rarely significantly compromised by preanalytical variables in the biospecimen “life cycle” (see Figure 1). Therefore, little, if any, attention needed to be directed toward the standardization, control, and tracking of preanalytical variables. With molecular assessment now standard for many cancers and increasingly required for many others, the bar for the molecular quality of cancer biospecimens has gone up and has given preanalytics a much greater level of significance.

Figure 1. The life cycle of a surgical resection specimen

Figure 1. The life cycle of a surgical resection specimen

Preanalytical variables, for any patient biospecimen, include all of the processing, handling, and transport procedures the specimen undergoes, along with all of the physical and environmental factors to which it is exposed before being analyzed. Many of these variables have profound effects on the molecular quality of patient biospecimens but may have little or no effect on morphological parameters. Thus, historically, before molecular testing of patient specimens became standard practice, the bar for preanalytical variation was only as high as it needed to be for routine histopathology.

Despite the fact that the current level of attention to and control over preanalytical variables is wholly inadequate for molecular testing, it has never been changed appropriately to ensure the molecular integrity of patient specimens to meet the needs of precision oncology. Because professional perceptions about biospecimen stewardship, for both surgeons and pathologists, are still based largely on this historically low bar for biospecimen quality, there is an urgent need to change the culture of surgery and surgical pathology practice to ensure the control of specimen quality is a primary focus. Safeguarding the molecular quality of patient biospecimens is vital for precision oncology and must be regarded as an integral part of the professional responsibilities of surgeons and pathologists.

Cold ischemia time

One of the most important preanalytical variables starts in the operating room (OR) and is known as cold ischemia time—the period that elapses between removal of the tissue from the body by the surgeon and the fixing or freezing of the tissue (processes known as tissue stabilization) by the pathologist. During this time, the tissue is still viable and experiences major biological stress in the form of anoxia, nutrient deprivation, temperature change, and desiccation with subsequent changes in gene expression, protein translation and modification, and molecular degradation. Stabilization halts further biological activity or molecular degradation and represents a critical and time-sensitive step in tissue processing.

Cold ischemia time affects different classes of biomolecules in different ways, depending on the relative lability or stability of the molecular entity. However, cold ischemia time should always be as short as possible, but a maximum of one hour would be a reasonable goal that is both data-driven and practicable in the clinical setting.*

At present, the only enforced cold ischemia time in pathology practice comes from the American Society of Clinical Oncology/College of American Pathologists (ASCO-CAP) human epidermal growth factor receptor 2 (HER2) testing in breast cancer guidelines with a strong recommendation of time to fixative within one hour.* With the exception of this special case, cold ischemia times for cancer resection specimens can vary significantly—from minutes to days—and there are no requirements to record, let alone control, cold ischemia times for these specimens. Thus, the molecular quality of the vast majority of cancer resection specimens, and, therefore, their “fitness” for molecular testing, is largely or completely unknown at the time of analysis. When the molecular composition is altered and the quality of tissues is compromised, as often occurs as a result of cold ischemia-related factors, the molecular analysis data derived from the tissue is unreliable. In fact, the quality of the molecular data derived from a biospecimen can never be higher than the quality of the molecular analytes in that specimen.

The ultimate risk, of course, is that incorrect molecular analysis data generated from compromised tissue specimens will lead directly or indirectly to inappropriate or erroneous patient management decisions, or worse, fatal errors in judgment. In a setting in which the results of a companion diagnostic test are the gateway to the informed use of a specific (often costly) therapy, the stakes are high, and neither a false negative nor a false positive can be tolerated.

The quality gap

The case for extending control over cold ischemia time for every surgical resection specimen from every cancer patient would seem to be evident given the potential detrimental impact of this variable on molecular integrity and the increasing focus on specimen-derived molecular data. Nevertheless, most cancer resection specimens fall into a quality gap in the chain of custody from surgeon to pathologist, largely due to the aforementioned problem in professional perception and practice.

Specifically, the issue has to do with a surgeon’s perception that safe and effective excision of the diseased tissue is his or her primary responsibility while the custodianship of the resected tissue is not part of this duty. Surgeons typically delegate custodianship to OR staff and other hospital staff who may handle/carry the specimen, place it in a holding station (often a refrigerator), or deliver it to the pathology department. No records are required to document the variations in physical conditions to which specimens are subjected nor is the time lapse between resection and delivery to pathology recorded.

Pathologists, for their part, typically consider the specimen to enter their domain of professional responsibility only after it is delivered to their department. Their knowledge of the events preceding the delivery of the specimen to the pathology department, including the exact time of resection and removal of the specimen (the start of cold ischemia time), is usually minimal to nonexistent. However, it is important to note that even after the specimen has been accessioned to pathology, there is no requirement to control or record the duration or conditions of the cold ischemia time that elapses prior to gross examination and tissue stabilization. The challenge of controlling and recording cold ischemia time can only be met if surgeons and pathologists alike change these practices and jointly share the responsibility for custodianship of the specimen.

Joint dialogue

Pathologists are stepping forward to address their part of the preanalytics challenge, but much remains to be done, both inside and outside of the discipline of pathology. Although the ultimate goal is a sweeping improvement in the molecular integrity of all resection specimens for all cancer patients, this milestone cannot be achieved without the collaborative efforts of surgeons.

Initiating a culture change

The ASCO-CAP and the American College Surgeons, under the auspices of the Commission on Cancer (CoC), have initiated a joint dialogue emphasizing the importance of surgeons and pathologists working together to improve the molecular integrity of resection specimens. The CoC has appointed Bruce Averbook, MD, FACS, a coauthor of this article, as its representative to this effort with the goal of defining coordinated surgical and pathology practices that ensure coordinated custodianship for surgical resection specimens in routine practice. The CoC and the ASCO-CAP agree that closure of the quality gap for surgical resection specimens is essential for high-quality care of cancer patients and that this effort is the joint responsibility of surgeons and pathologists.

Changing the cultures of both the OR and surgical pathology practice is a daunting challenge. Not only will it require educational initiatives for surgeons and surgical pathologists, but for other essential staff such as nurses, radiology staff (for example, for breast tissue undergoing specimen imaging), and pathology assistants as well. The time during which the resection specimen sits at room temperature after removal, the length of time required for packaging, labeling, and transport, and the number of handoffs between carriers/transporters all become important considerations for systems analysis at any institution. The surgeon will need to be aware of, and seek to remedy, these issues at his or her institution, which will vary significantly depending on practice setting.

It will be essential to always track and record the time from tissue resection/harvest to the tissue stabilization step and to foster good communication between the OR and the pathology team. In institutions with high volumes of cancer surgery, it may even be necessary to have dedicated personnel who serve as “tissue navigators” and have specimen handling, transport, and annotation (recording of key preanalytical factors) as their primary role. Alternatively, this role might be developed as a specialty focus for existing staff, such as pathology assistants.

Routine logistical and operational issues will need to be addressed on an institution-specific basis to accomplish the goal of controlling cold ischemia time. Special or unusual circumstances that could affect cold ischemia time may need to be addressed as well. For example, it may no longer be acceptable to keep resected cancer specimens in a holding refrigerator overnight and deliver them to the pathologist in the morning for processing. This revised process would include surgical specimens resected after usual business hours, such as add-on cases or emergency cancer cases (for example, bowel obstruction or perforation). Wire localization procedures or any localization step that requires radiological confirmation by tissue re-imaging after harvest/resection can increase cold ischemia time both in time for imaging and time for transport from the OR to radiology and back and then on to pathology.

A variety of other challenges also may impede prompt specimen processing, including the availability of personnel for transporting specimens as soon as they are ready for delivery or the existence of long distances between the OR and the pathology department. In addition, the lack of availability of pathologists at satellite outpatient surgery centers may need to be addressed at some institutions. Lastly, the transplant patient presents another urgent circumstance that will require more flexibility on the part of the pathology team to be available as required.

A step forward

Closure of the quality gap for cancer resection specimens is an essential step forward for quality practice of precision oncology, but it will also have widespread effects on translational research. Most of the biospecimens that are used in correlative scientific studies of patients in clinical trials and that contribute directly or indirectly to biomarker and/or new product development come from clinically derived samples. Thus, improving the molecular quality and consistency of cancer resection specimens will simultaneously improve the quality of patient care and translational research with obvious benefits for cancer patients, both present and future.

Though challenging, closing this quality gap falls clearly into the category of “the right thing to do.” CoC accreditation standards may change in the future with regard to documentation of cold ischemia time, timely specimen management, and compliance with a goal of tissue stabilization within an hour. We need to start now.


*Wolff AC, Hammond ME, Hicks DG, et al. Recommendations for human epidermal growth factor receptor 2 testing in breast cancer: American Society of Clinical Oncology/College of American Pathologists Clinical Practice Guideline Update. J Clin Oncol. 2013;31(31):3997-4013.

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