Challenges in Diagnosing Medication Resins in Surgical Pathology Specimens: A Crystal-Clear Review Guide

To date, 3 types of resins have been identified (Figure 1). The bile acid sequestrants (BAS) target bile acids and are mainly used to treat diarrhea.²  They have been used safely for more than 43 years and are considered biologically inert. The BAS are usually bright orange on H&E, with a rectangular shape and a smooth or glassy texture. They can occasionally feature minute, pink dotlike inclusions. The BAS include colesevelam (Welchol, Daiichi Sankyo Inc, Tokyo, Japan), colestipol (Colestid, Pfizer Inc, New York, New York), and cholestyramine (LoCholest, Warner Chilcott Inc, Rockaway, New Jersey; Prevalite, Upsher-Smith Laboratories, Maple Grove, Minnesota; and Questran, Par Pharmaceutical, Woodcliff Lake, New Jersey). Because these medications are morphologically identical, they are best diagnosed as “bile acid sequestrants,” unless a chart review is performed to verify the specific BAS administered.² 

Kayexalate (Concordia International Corp, Oakville, Ontario, Canada), also known as sodium polystyrene sulfonate, is a potassium-binding agent used in patients with renal failure. It is rectangular in shape, purple on H&E, and has “fish scales,” or internal demarcations that appear similar to the external surface of a fish. Kayexalate is well known for causing sometimes fatal bowel ischemia, ulcerations, necrosis, pseudotumors, and perforations.^3–15  The pathogenic properties of Kayexalate have long been attributed to its hyperosmotic sorbitol diluent and not the resins themselves. However, recent rat studies demonstrated that Kayexalate alone can result in fatal colonic necrosis, suggesting that the resins themselves may be pathogenic.¹⁶  Similar conclusions have been drawn from a meta-analysis of 58 cases of adverse events in patients on Kayexalate with or without sorbitol.⁵ 

Sevelamer (Renvela and Renagel, Sanofi SA, Paris, France) is the newest member of the resin family. It is a phosphate-lowering medication used in patients with renal failure.¹⁷  It is rectangular in shape and usually 2-toned in color on H&E, with a pink center and yellow edges; it also has fish scales. In the initial description, sevelamer was associated with mucosal injury in a dose-dependent manner, suggesting it may have the potential to cause significant injury.¹⁷  Subsequent reports have reported similar associations.^18–24 

Nonclassical resin morphology represents a common diagnostic challenge. The most common resin pitfalls are discussed below.

Sevelamer can be variably brown, deep red, or light purple, thereby overlapping in appearance with both the BAS and Kayexalate (Figure 2). In addition, the BAS can be black, deep red, or dull orange, overlapping in color with sevelamer. Potential factors influencing the resin coloration include variable substrate binding and the background pH.^17–25 

Historically, considerable weight has been placed on the presence or absence, size, and shape of fish scales in discerning the resins from each other. However, similar fish scale patterns can be reproduced with histologically processed gallbladder calculi, dystrophic calcifications, unspecified luminal contents (possibly food), and large BAS fragments (Figures 3 through 5). This raises the possibility that the fish scales are a nonspecific histologic artifact from knife-cutting of thick tissue. To those unfamiliar with these atypical presentations, fish scales in large BAS resins can lead to a misdiagnosis of Kayexalate or sevelamer, and cases of Kayexalate lacking fish scales could be erroneously overlooked. Moreover, in the initial description of sevelamer,¹⁷  its fish scales were reported as large and broad with curvilinear points of intersection, and those of Kayexalate were described as narrow with perpendicular lines of intersection. As experience with these resins has grown, we now know that the shape of the fish scales is not specific to the resin type. Kayexalate, sevelamer, and BAS can have either narrow or broad fish scales, although fish scales in BAS are uncommon and almost always limited to large resins or thick sections (Figures 4 and 5).

Classically, the resins are described as crystalline or rectangular in shape. More recently, rounded structures have been occasionally described with BAS, specifically colestipol²⁶  (Figure 6).

The resins are almost always identified along the tubular GI tract, but they can occasionally be identified in unusual locations. We have seen cutaneous resin deposition in ostomy resection specimens. We have also observed resins in the gallbladder of a patient with a history of biliary stenting and in a separate surgical resection of a necrotic pancreas. Theoretically, the resins may have escaped the tubular GI tract in these cases by way of the adjoining bowel segment, stent manipulation, and fistula formation between the necrotic pancreas and stomach. Regardless of their location, recognition is important to communicate with the clinician.

As illustrated above, almost every “rule” of classic resin morphology can be broken. To further compound these diagnostic challenges, it is not uncommon to have more than one resin in an individual case (Figure 5). The best way to sort out these complicated cases is a combination of the H&E morphology with a firm familiarity of the spectrum of resin morphology. If ancillary studies are desired, our experience is that the acid-fast bacillus special stain is the most reliable ancillary tool; it stains BAS dull yellow, Kayexalate black, and sevelamer magenta.^2,27,28  We find periodic acid–Schiff too inconsistent to be helpful.² 

Another helpful tip is to scan all of the resin fragments present in a slide. The atypical presentations discussed above are usually only focal, with the more characteristic resin morphology more easily seen in the surrounding resin fragments. For example, fish scales are usually restricted to large BAS resins and thick sections, with the more typical smooth BAS texture consistently seen in the smaller fragments²  (Figure 4, C). Above all, a low threshold for a chart review or discussion with the clinician about the medication list can be reassuring.

The most important reason to recognize the resins is to alert the clinician to the potentially dangerous effects of Kayexalate and sevelamer when mucosal injury is seen. Resins are also worthwhile to recognize because they can serve as clues to other critical diagnoses. For example, BAS are used to treat diarrhea and should serve as clues to look for subtle causes of diarrhea, such as cytomegalovirus, mycophenolate injury, and graft-versus-host disease. Similarly, Kayexalate and sevelamer are used in the setting of renal failure and should serve as clues to look for other diagnoses associated with renal failure, such as amyloidosis, cytomegalovirus, herpes simplex virus, Candida, and mycophenolate (Figure 7).

Atypical presentations and incomplete or inaccessible medication lists can serve as barriers to resin identification. Our approach is always to report the resins when they are present (Figure 8). Based on the wide spectrum of morphology, recognition that we are at the very beginning of understanding of these medications, and our personal experience, our approach is to topline the specific resin only when the morphology and location are classic and can be confirmed by the clinician or review of the medication record. Otherwise, we recommend a topline descriptive diagnosis followed by a note that discusses the favored diagnosis along with the risk of associated mucosal injury. As an aside, at one point, all BAS were called “cholestyramine” in our reports. When a displeased clinician requested an amendment because the patient had never been prescribed cholestyramine, we learned to adopt a more descriptive and open-minded approach to the resins, including medication review when possible. This interaction also ultimately led to the discovery that BAS represent a number of distinct medications that are histologically identical.² 

We consider Kayexalate or sevelamer associated with mucosal injury a clinical emergency, and we document the verbal conveyance of this critical information to the clinician in an attempt to ensure that the patient is carefully monitored to prevent potential deleterious outcomes. However, if Kayexalate or sevelamer is seen without mucosal injury, we simply report the finding and explain in the note the known associations with mucosal injury (but we do not emergently contact the clinician). Examples are detailed below.

Colon, biopsy: “Sevelamer resins identified in otherwise unremarkable colonic mucosa, See note.”

In the small series available, sevelamer was associated with mucosal injury in a dose-dependent manner. Clinical correlation was suggested.¹⁷ 

“Eosinophilic crystals identified, See note.”

No clinical notes are available at time of slide review. Eosinophilic crystals are seen on H&E. These structures are yellow on acid-fast bacillus and are suggestive of BAS (colesevelam [Welchol], colestipol [Colestid], cholestyramine [LoCholest, Prevalite, Questran]). In the small series available, BAS had no established role in causing mucosal damage.² 

“Purple crystals identified within pancreatic pseudocyst, See note.”

Scattered purple crystals with fish scales are seen on H&E. These structures are black on acid-fast bacillus and suggestive of Kayexalate. Kayexalate has been associated with significant mucosal injury, including ischemia, ulcerations, necrosis, and perforations. Clinical correlation suggested. Dr [pathologist] verbally discussed these findings with Dr [clinician] on [date] at [time].^3,6,7 

In summary, identification of colorful medications in the tubular GI tract will only continue to increase as endoscopy rates and the incidence of polypharmacy rise. The resins are commonly encountered medications that can be diagnosed on H&E with awareness of the diagnostic pearls and pitfalls discussed above. Timely diagnosis can be life-saving in the cases of Kayexalate and sevelamer when the resins are seen in association with mucosal injury; BAS are biologically inert. Recognition of the resins may also provide important clues to other critical diagnoses. Lastly, this review emphasizes effective reporting strategies with an emphasis on conveying the risk of injury in the pathology report.