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

Resins are nonabsorbable medications that facilitate ion exchange. They are most commonly orally ingested and can be identified anywhere along the tubular gastrointestinal (GI) tract and in the lung, in cases of aspiration. (1) Because the resins have differential capabilities to cause (sometimes) fatal mucosal injury, recognition and timely diagnosis can be life-saving. A 2016 online survey administered through the Rodger C. Haggitt Gastrointestinal Pathology Society and Twitter revealed that 75% of 99 pathologists with a GI subspecialized interest had never seen resin administration documented on the pathology requisition. As a result, it is critical for pathologists to be aware of the typical and atypical presentations of medication resins. Of those who answered the survey, 24% incorrectly identified the classic resin appearance on hematoxylin-eosin (H&E) staining. Below is a review of the resins' classic morphology, common diagnostic pitfalls, helpful ancillary studies, and reporting strategies.

CLASSIC MORPHOLOGY

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)

ATYPICAL MORPHOLOGY

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

H&E Color Is (Sometimes) Overrated

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)

Fish Scales Are (Sometimes) Overrated

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).

Resin Shape Is (Sometimes) Overrated

Classically, the resins are described as crystalline or rectangular in shape. More recently, rounded structures have been occasionally described with BAS, specifically colestipol (26) (Figure 6).

Location Is (Sometimes) Overrated

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.

ANCILLARY STUDIES

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 fragments (2) (Figure 4, C). Above all, a low threshold for a chart review or discussion with the clinician about the medication list can be reassuring.

RESINS AS CLUES TO CRITICAL DIAGNOSES

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).

RESIN REPORTING

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.

Example 1: Classic Sevelamer Morphology and Site, No Associated Injury, Sevelamer Administration Confirmed by Review of the Medication List; Similar Approach For Analogous Case of Kayexalate.--Colon, biopsy: "Sevelamer resins identified in otherwise unremarkable colonic mucosa, See note."

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

Example 2: Classic BAS Morphology With No Clinical Confirmation Available, or Atypical BAS Morphology.--"Eosinophilic crystals identified, See note."

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)

Example 3: Classic Kayexalate Morphology With Associated Injury but No Clinical Confirmation, or Atypical Kayexalate Morphology, or Atypical Location.--"Purple crystals identified within pancreatic pseudocyst, See note."

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)

CONCLUSIONS

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.

Please Note: Illustration(s) are not available due to copyright restrictions.

References

(1.) Mukhopadhyay S, Katzenstein AL. Pulmonary disease due to aspiration of food and other particulate matter: a clinicopathologic study of 59 cases diagnosed on biopsy or resection specimens. Am J Surg Pathol. 2007; 31(5):

752-759.

(2.) Arnold M, Swanson BJ, Crowder CD, et al. Colesevelam and colestipol: novel medication resins in the gastrointestinal tract. Am J Surg Pathol. 2014; 38(11):1530-1537.

(3.) Abraham SC, Bhagavan BS, Lee LA, Rashid A, Wu TT. Upper gastrointestinal tract injury in patients receiving kayexalate (sodium polystyrene sulfonate) in sorbitol: clinical, endoscopic, and histopathologic findings. Am J Surg Pathol. 2001; 25(5):637-644.

(4.) Foresti V. Intestinal obstruction due to kayexalate in a patient concurrently treated with aluminum hydroxide and morphine sulfate. Clin Nephrol. 1994; 41(4):252.

(5.) Harel Z, Harel S, Shah PS, Wald R, Perl J, Bell CM. Gastrointestinal adverse events with sodium polystyrene sulfonate (Kayexalate) use: a systematic review. Am J Med. 2013; 126(3):264.e9-24.

(6.) Lillemoe KD, Romolo JL, Hamilton SR, Pennington LR, Burdick JF, Williams GM. Intestinal necrosis due to sodium polystyrene (Kayexalate) in sorbitol enemas: clinical and experimental support for the hypothesis. Surgery. 1987; 101(3):267-272.

(7.) Rashid A, Hamilton SR. Necrosis of the gastrointestinal tract in uremic patients as a result of sodium polystyrene sulfonate (Kayexalate) in sorbitol: an underrecognized condition. Am J Surg Pathol. 1997; 21(1):60-69.

(8.) Scott TR, Graham SM, Schweitzer EJ, Bartlett ST. Colonic necrosis following sodium polystyrene sulfonate (Kayexalate)-sorbitol enema in a renal transplant patient: report of a case and review of the literature. Dis Colon Rectum. 1993; 36(6):607-609.

(9.) Wootton FT, Rhodes DF, Lee WM, et al. Colonic necrosis with Kayexalatesorbitol enemas after renal transplantation. Ann Intern Med. 1989; 111(11):947-949.

(10.) Bui M, Chou SY, Faubert P, Loarte P, Cohen R. Resin-induced colonic pseudotumor: rare complication from chronic use of potassium binders in a hemodialysis patient. Case Rep Nephrol. 2016; 2016:3692086.

(11.) Rodriguez-Luna MR, Fernandez-Rivera E, Guarneros-Zarate JE, Tueme-Izaguirre J, Hernandez-Mendez JR. Cation exchange resins and colonic perforation: what surgeons need to know. Int J Surg Case Rep. 2015; 16:102-105.

(12.) Akagun T, Yazici H, Gulluoglu MG, Yegen G, Turkmen A. Colonic necrosis and perforation due to calcium polystyrene sulfonate in a uraemic patient: a case report. NDT Plus. 2011; 4(6):402-403.

(13.) Dunlap RH, Martinez R. Total colectomy for colon perforation after Kayexalate administration: a case report and literature review of a rare complication. J Surg Case Rep. 2016; 2016(10):pii: rjw167.

(14.) Trottier V, Drolet S, Morcos MW. Ileocolic perforation secondary to sodium polystyrene sulfonate in sorbitol use: a case report. Can J Gastroenterol. 2009; 23(10):689-690.

(15.) Bomback AS, Woosley JT, Kshirsagar AV. Colonic necrosis due to sodium polystyrene sulfate (Kayexalate). Am J Emerg Med. 2009; 27(6):753.e1-2.

(16.) Ayoub I, Oh MS, Gupta R, McFarlane M, Babinska A, Salifu MO. Colon necrosis due to sodium polystyrene sulfonate with and without sorbitol: an experimental study in rats. PLoS One. 2015; 10(9):e0137636.

(17.) Swanson BJ, Limketkai BN, Liu TC, et al. Sevelamer crystals in the gastrointestinal tract (GIT): a new entity associated with mucosal injury. Am J Surg Pathol. 2013; 37(11):1686-1693.

(18.) Amer S, Nguyen C, DePetris G. Images of the month: gastric pneumatosis due to sevelamer-mediated necrosis. Am J Gastroenterol. 2015; 110(6):799.

(19.) Desai M, Reiprich A, Khov N, Yang Z, Mathew A, Levenick J. Crystal-associated colitis with ulceration leading to hematochezia and abdominal pain. Case Rep Gastroenterol. 2016; 10(2):332-337.

(20.) Okwara C, Choi C, Park JY. Sevelamer-induced colitis presenting as a pseudotumor. Clin Gastroenterol Hepatol. 2015; 13(7):A39-A40.

(21.) Tieu C, Moreira RK, Song LM, Majumder S, Papadakis KA, Hogan MC. A case report of sevelamer-associated recto-sigmoid ulcers. BMC Gastroenterol. 2016; 16:20.

(22.) Yamaguchi T, Ohyama S, Furukawa H, et al. Sigmoid colon diverticula perforation associated with sevelamer hydrochloride administration: a case report. Ann Med Surg (Lond). 2016; 10:57-60.

(23.) Chintamaneni P, Das R, Kuan SF, Kermanshahi TR, Hashash JG. Hematochezia associated with Sevalamer-induced mucosal injury. ACG Case Rep J. 2014; 1(3):145-147.

(24.) Madan P, Bhayana S, Chandra P, Hughes JI. Lower gastrointestinal bleeding: association with Sevelamer use. World J Gastroenterol. 2008; 14(16): 2615-2616.

(25.) Chaplin AJ. The use of histological techniques for the demonstration of ion exchange resins. J Clin Pathol. 1999; 52(10):776-779.

(26.) Gonzalez RS, Schwartz DA, Shi C. Colestipol granules in the colon: macroscopic and microscopic findings. Histopathology. 2015; 67(1):141-142.

(27.) Voltaggio L, Lam-Himlin D, Limketkai BN, Singhi AD, Arnold CA. Message in a bottle: decoding medication injury patterns in the gastrointestinal tract. J Clin Pathol. 2014; 67(10):903-912.

(28.) Arnold CA, Bhaijee F, Lam-Himlin D. Fifty shades of chronic colitis: noninfectious imposters of inflammatory bowel disease. Diagn Histopathol. 2015; 21(7):276-282.

Raul S. Gonzalez, MD; Stephen M. Lagana, MD; Oliver Szeto, MD; Christina A. Arnold, MD

Caption: Figure 2. The resin color on hematoxylin-eosin is sometimes overrated. Sevelamer is classically 2-toned, with a pink center and yellow edges (see Figure 1). It can occasionally appear variably brown (not shown), deep red (A), or light purple (B), and overlap with both Kayexalate and bile acid sequestrants (BAS). The BAS are classically bright orange, but they can appear black in thick sections (C) or dull orange (D), the latter overlapping in color with sevelamer (hematoxylin-eosin, original magnifications31000 [A, C, and D] and3400 [B]).

Caption: Figure 3. Fish scales are sometimes overrated, part 1. Fish scales can be seen in histologically processed gallbladder calculi (A), dystrophic calcifications (B), unspecified luminal material (favor food; C), and occasionally in large bile acid sequestrant fragments (see Figures 4, C and F, and 5), suggesting that fish scales are a histologic artifact of knife-cutting. Alternatively, rarely Kayexalate lacks fish scales (D). Specimen ink is also a common resin mimic; it appears with a granular consistency at high power (E and F) (hematoxylin-eosin, original magnification X400).

Caption: Figure 4. Fish scales are sometimes overrated, part 2. Kayexalate, sevelamer, and bile acid sequestrants (BAS) can have either narrow fish scales with perpendicular points of intersection (A, B, and C, respectively), or can have broad fish scales with curvilinear points of intersection (D, E, and F, respectively) (hematoxylin-eosin, original magnifications X1000 [A, B, and D through F] and X400 [C]).

Caption: Figure 5. Beware that patients with complications may have more than one resin onboard. This fatal case of ischemic colitis showed abundant Kayexalate (arrow) and bile acid sequestrant (BAS) resins (bracket, asterisks) at the perforation site. Note that both the Kayexalate and the large BAS resin (bracket) have broad fish scales, a common diagnostic pitfall seen in large or thick BAS fragments. The smaller BAS resins retain the characteristic smooth texture free of fish scales (asterisks) (hematoxylin-eosin, original magnification X400).

Caption: Figure 6. Most resins appear rectangular or crystalline in shape, but the granule form can occasionally appear round, as depicted in this case of colestipol (Colestid). Note that bile acid sequestrants may occasionally feature minute dotlike bright pink inclusions (arrows) (hematoxylin-eosin, original magnification X1000).

Caption: Figure 7. Resins can be clues to other critical diagnoses. Both sevelamer and Kayexalate are used in patients with renal failure and should prompt consideration of other related diagnoses, such as amyloidosis, as seen in this case. The arrows highlight sevelamer (A). Note the sevelamer color is atypical on hematoxylin-eosin and appears dark red, as opposed to its classic 2-toned color with a pink center and yellow edges (compare with Figure 1). The adjoining amyloid is highlighted with brackets (B) and is bright orange on a Congo Red stain under direct light (C) (hematoxylin-eosin, original magnifications X100 [A] and X400 [B]; original magnification X400 [C]).

Caption: Figure 8. A diagnostic algorithm to resin reporting. Abbreviation: H&E, hematoxylin-eosin.
Figure 1. Classic features of medication resins. Welchol: Daiichi
Sankyo Inc, Tokyo, Japan; Colestid: Pfizer Inc, New York, New York;
LoCholest: Warner Chilcott Inc, Rockaway, New Jersey; Prevalite:
Upsher-Smith Laboratories, Maple Grove, Minnesota; Questran: Par
Pharmaceutical, Woodcliff Lake, New Jersey; Kayexalate: Concordia
International Corp, Oakville, Ontario, Canada; and Renvela and
Renagel: Sanofi SA, Paris, France. Abbreviations: AFB, acid-fast
bacillus; H&E, hematoxylin-eosin (H&E, original magnification
X1000).

Also Known    Colesevelam         Kayexalte   Renagel,
As            (Welchol),                      Renvela
              colestipol
              (Colestid), and
              cholestyramine
              (LoCholest,
              Prevalite, and
              Questran)

Target ion    Bile acids          Potassium   Phosphate

Clinical      Diarrhea            Chronic     Chronic
history                           renal       renal
                                  failure     failure

Mucosal       No                  Yes         Possible
injury

Fish-scales   None                Yes         Yes

H&#           Bright orange       Purple      2-toned
                                              pink/yellow

AFB           Dull yellow         Black       Magenta
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Author:Gonzalez, Raul S.; Lagana, Stephen M.; Szeto, Oliver; Arnold, Christina A.
Publication:Archives of Pathology & Laboratory Medicine
Article Type:Report
Date:Sep 1, 2017
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