PAP/NGC Program Review
Jonathan H. Hughes, MD, PhD
The field of gastroenterology was revolutionized in the 1980s
by the attachment of ultrasound probes to endoscopes. The resulting technique
of endoscopic ultrasound, or EUS, permitted high-resolution imaging of lesions
in the gastrointestinal wall and adjacent organs. Until recently, a major limitation
of EUS was the inability of ultrasonographic visualization alone to differentiate
benign processes from malignant lesions. This drawback has been overcome by
the advent of futher technological advances that couple EUS visualization with
the ability to sample mass lesions by fine-needle aspiration. Endoscopic ultrasound-guided
fine-needle aspiration, or EUS-FNA, now allows the endoscopist to perform real-time
imaging and to obtain guidance for the sampling of lesions using 19- or 25-gauge
The potential diagnostic benefits of EUS-FNA are obvious. This new technology allows endoscopists and pathologists to work together to diagnose lesions in the gastrointestinal tract, periluminal lymph nodes, pancreas and hepatobiliary tree, left kidney, spleen, and adrenal glands. This low-morbidity technique makes it possible to detect disease, and document the extent of disease, in patients who previously would have required a major surgical procedure. Moreover, EUS-FNA permits the sampling of lesions that would be too small or difficult to localize by traditional percutaneous FNA. The technique is becoming increasingly popular in the United States and other parts of the world, and it seems likely that it will eventually become the standard of practice for diagnosing and staging neoplasms of the gastrointestinal tract and associated organs.
However, EUS-FNA also presents a unique set of challenges to cytologists, even those cytologists who are well versed in the interpretation of the more commonplace types of CT-guided and fluoroscope-guided FNAs. The purpose of this article is to describe, from the cytologist’s perspective, some of the unique aspects of EUS-FNA specimens, and to highlight the challenges that these specimens present cytology laboratories.
Sample procurement and processing
As is the case with all pathology specimens, the specimen must be processed optimally to maximize the diagnostic yield of the procedure. From the pathologist’s perspective, the initial handling of EUS-FNA specimens is not significantly different from that of other types of radiologically guided FNAs. As has been previously demonstrated with radiologically guided FNAs, the presence of a cytopathologist or cytotechnologist in the EUS suite at the time of the procedure reduces the frequency of nondiagnostic specimens. Chang and colleagues showed that the presence of a cytopathologist in the endoscopy suite resulted in an adequate specimen in 100 percent of cases, as compared with only 71 percent when a cytopathologist was not present.1 In separate studies, Jhala, et al and Voss, et al demonstrated an increase in diagnostic accuracy for identifying endocrine tumors of the pancreas when a cytopathologist was present in the endoscopy suite to perform immediate assessment.2,3 The presence of a cytopathologist at the EUS-FNA procedure also permits appropriate triage of the aspiration material for ancillary studies, such as cultures, immunohistochemistry, and flow cytometry studies.
Time and cost considerations
While there is ample evidence that the presence of a cytopathologist at the EUS-FNA procedure increases the procedure’s diagnostic yield, this benefit must be weighed against the practical considerations of pathologist availability and time constraints. While these issues are considerations in all types of FNA procedures involving assistance by the cytopathologist, there is evidence to suggest that EUS-FNA may be even more time-consuming for the pathologist than other types of radiologically assisted procedures.
In an elegant study examining the impact of pathologist-assisted FNAs on laboratory staffing and cost, Layfield and colleagues showed that endoscopic aspirations required more cytopathologist time (56.2 minutes on average) than a CT-guided FNA (48.7 minutes), an ultrasound-guided biopsy (44.4 minutes), a clinic FNA performed by a pathologist (42.5 minutes), or a clinic FNA performed by a clinician (34.7 minutes). 4 In this same study, the average amount of pathologist time required to perform a frozen section was only 15.7 minutes. In my personal anecdotal experience, EUS-FNA is more time-consuming, requires more needle passes, and results in more slides to be examined than CT-guided or ultrasound-guided FNAs. Layfield, et al translated the effects of the significant pathologist time required for these procedures into meaningful economic terms, as they used Medicare rate schedules and the average procedure times listed in this article to demonstrate that the time cost of an EUS-FNA procedure exceeds the average Medicare compensation by $40 to $50.
Clearly, the time required by the pathologist to participate in EUS-FNA procedures must be carefully considered when establishing a protocol with the endoscopists. The ability to absorb this cost will vary among laboratories. At the very least, the endoscopist should be made aware of the significant time commitment required by the pathologist, so that the procedure(s) can be streamlined as much as possible. The endoscopy staff should be instructed to call the pathologist only when the FNA is about to be performed. If possible, procedures should be scheduled back to back or simultaneously so that fewer trips to the endoscopy suite are required. It may also be helpful to have a permanent microscope with staining apparatus in the endoscopy area, so that the cytopathologist does not have to transport those items for each procedure. In some laboratories, personnel may be available (cytotechnologists, pathology residents) who can prepare and stain smears, thereby decreasing the amount of time required of the pathologist.
Utility and diagnostic accuracy
EUS-FNA can be used to sample a wide variety of intramural and extramural structures of the gastrointestinal tract. Currently, the technique is most often employed to sample pancreatic lesions and lymph nodes. However, it has also been used successfully to obtain diagnostic material from the esophagus, stomach, small bowel, colon, hepatobiliary tree, left kidney, spleen, and adrenal glands. Numerous published studies examining the utility of EUS-FNA in a number of different organ systems show that the technique results in a high level of diagnostic accuracy. Moreover, EUS-FNA can yield diagnostic tissue in patients for whom other sampling modalities, such as endoscopic forceps biopsy or percutaneous FNA, were unsuccessful.
Although the cytologic features of EUS-FNA specimens are generally similar to those of percutaneous FNA, there are important differences and potential pitfalls. Because EUS-FNA specimens are approached from inside the gastrointestinal tract, the needle passes through and samples normal tissues that are not usually present in a percutaneous FNA specimen. Potential organ-specific pitfalls are as follows:
Lymph nodes. Contamination of a lymph node FNA by normal gastrointestinal mucosa is an important diagnostic pitfall. For example, EUS-FNA of a perigastric lymph node might produce a specimen containing sheets of normal gastric mucosa that could, if the pathologist is not wary, result in a false-positive interpretation of metastatic carcinoma. Because EUS-FNA is frequently used to stage lymph nodes in patients with established gastrointestinal malignancies, the tendency to overdiagnose benign mucosa as metastatic carcinoma can be great. An even more difficult pitfall is when the FNA needle samples an area of high-grade dysplasia in the enteric mucosa en route to the lymph node target.
Pancreas. Jhala has described many of the interpretive pitfalls associated with EUS-FNA of the pancreas. Depending on the topographic location of the lesion in the pancreas, the EUS-FNA will sample different types of normal gastrointestinal tract structures. For head/uncinate lesions, the transmural approach is usually through the duodenum, which may result in large numbers of cohesive duodenal glandular epithelium with goblet cells. For lesions in the body/tail, the endoscopist will usually employ a transgastric approach, and the sample may contain large numbers of parietal cells or superficial gastric cells. To avoid interpretive errors, the pathologist needs to be aware of these different types of contaminating normal cells. For example, an aspirate of a pancreatic pseudocyst that contains a large amount of contaminating gastric or duodenal mucosa could easily be misinterpreted as a mucinous cystic neoplasm.
Gastrointestinal tract. EUS-FNA is an excellent technique for sampling mural masses of the gastrointestinal tract, particularly submucosal lesions that are not accessible with conventional endoscopic forceps or too difficult to localize by percutaneous FNA. EUS-FNA is increasingly being used for the diagnosis of gastrointestinal stromal tumors, or GISTs, and other spindle cell tumors (for example, leiomyomas), as the technique permits sampling of deep-seated mural lesions. Pathologists need to be careful to avoid over-interpreting normal gastrointestinal smooth muscle as a neoplastic process. Also, because differentiation of GIST from other spindle cell tumors has important therapeutic implications, immunohistochemical (CD117, CD34, smooth muscle actin, muscle specific actin, S-100 protein) stains should be used to distinguish GISTs from other primary spindle cell tumors. Finally, the pathologist should remain aware that some spindle cell neoplasms of the gastrointestinal tract may be metastatic lesions; spindle cell melanoma is a classic example of a metastatic lesion that may be misinterpreted as GIST.
Biliary tract. The pitfalls associated with EUS-FNA of the biliary tract are similar to those associated with conventional biliary tract cytology. Specifically, reactive changes associated with bile duct stents and inflammatory conditions may be interpreted as malignant.
Spleen, adrenal glands, left kidney, and other organs. While EUS-FNA of these organs has been described, most of the published reports are small series or case reports, so that it is difficult to draw conclusions about the most common pitfalls. Nonetheless, EUS-FNA appears to be an effective technique for sampling these organs. It would seem that over-interpretation of contaminating normal enteric mucosa as carcinoma would be an important pitfall, particularly, for example, in patients undergoing adrenal FNA for staging of lung adenocarcinoma.
EUS-FNA has revolutionalized the practice of gastrointestinal medicine and is rapidly becoming the technique of choice for sampling deep-seated lesions that were previously accessible only by laparotomy. Although the benefits of EUS-FNA to the patient and endoscopist are obvious, it presents many challenges for pathologists. The technique can be time-consuming and therefore requires an organized endoscopy service with good communication between endoscopist and pathologist so that the demands on the pathology laboratory and the pathologist’s time are minimized. There are also important issues related to reimbursement, which each laboratory will have to consider when developing the EUS-FNA service. Finally, the interpretation of EUS-FNA specimens is fraught with pitfalls, most of which are the result of contamination of the specimen by normal enteric mucosal elements. Awareness of these pitfalls can improve diagnostic accuracy and prevent false-positive diagnoses.
- Chang KJ, Katz KD, Durbin TE, et al. Endoscopic ultrasound-guided fine-needle
aspiration. Gastrointest Endosc. 1994;40:694-699.
- Jhala NC, Jhala DN, Chhieng DC, Eloubeidi MA, Eltoum IA. Endoscopic ultrasound-guided
fine-needle aspiration. A cytopathologist’s perspective. Am J Clin Pathol.
- Voss M, Hammel P, Molas G, et al. Value of endoscopic ultrasound guided
fine needle aspiration biopsy in the diagnosis of solid pancreatic masses.
- Layfield LJ, Bentz JS, Gopez EV. Immediate on-site interpretation of fine-needle
aspiration smears: a cost and compensation analysis. Cancer. 2001:93:
- Vander Noot MR, Eloubeidi MA, Chen VK, et al. Diagnosis of gastrointestinal
tract lesions by endoscopic ultrasound-guided fine-needle aspiration biopsy.
Cancer Cytopathol. 2003;102: 157-163.
Dr. Hughes, a member of the CAP Cytopathology Committee, is staff pathologist
at Laboratory Medicine Consultants, Las Vegas.