With the increasing development and use of iatrogenic agents, pathologists are encountering more novel foreign materials in retrieved gastrointestinal specimens. These colorful and unusual-appearing foreign materials can pose a diagnostic dilemma to those unaware of their morphology, especially if the relevant clinical history is lacking.
To discuss the histopathologic features, clinical scenarios and significance, and differential diagnosis of relatively recently described, yet quickly expanding, family of iatrogenic agents that can present as foreign materials in gastrointestinal specimens—pharmaceutical fillers (crospovidone and microcrystalline cellulose), submucosal lifting agents (Eleview and ORISE), lanthanum carbonate, hydrophilic polymers, OsmoPrep, yttrium 90 microspheres (SIR-Sphere and TheraSphere), and resins (sodium polystyrene sulfonate, sevelamer, and bile acid sequestrants).
We collate the findings of published literature, including recently published research papers, and authors' personal experiences from clinical sign-out and consult cases.
Correct identification of these iatrogenic agents is important because the presence of some novel agents can explain the histopathologic findings seen in the background specimen, and specific novel agents can serve as diagnostic clues to prompt the pathologist to consider other important and related diagnoses. Awareness of even biologically inert agents is important for accurate diagnosis and to avoid unnecessary and expensive diagnostic studies.
With increasing endoscopy and the increasing development and use of iatrogenic agents, pathologists encounter a mounting number of retrieved gastrointestinal (GI) specimens with characteristic foreign materials.1–9 As detailed in this review, some agents are critical to recognize because of their association with significant background mucosal injury, such as yttrium 90 (90Y) microsphere–associated radiation1,10,11 or sodium polystyrene sulfonate– or sevelamer-associated mucosal ulcers, ischemia, and pseudotumors.8,12–22 Other foreign materials are inconsequential, such as pharmaceutical fillers or bile acid sequestrants (BASs), but awareness of their typical histologic appearance is important to prevent misdiagnosis and triggering of unnecessary additional studies.2,4,7 Recognition of these agents can also serve as a helpful clue to carefully screen for other related processes, such as prompting consideration of amyloid in patients with lanthanum carbonate deposition, sodium polystyrene sulfonate, or sevelamer, as these agents are only prescribed in the setting of renal failure. This review focuses on the latest described iatrogenic agents that manifest as histologically identifiable foreign material(s) in the retrieved GI specimens: pharmaceutical fillers (crospovidone and microcrystalline cellulose [MCC]), submucosal lifting agents (Eleview, Aries Pharmaceuticals, and ORISE, Boston Scientific), lanthanum carbonate, hydrophilic polymers, OsmoPrep (Salix Pharmaceuticals, Raleigh, North Carolina), 90Y microspheres (SIR-Sphere, Sirtex Medical Inc, Sydney, Australia; TheraSphere, MDS Nordion, Ottawa, Ontario, Canada; and Biocompatibles UKI Ltd, Surrey, United Kingdom), and resins (sodium polystyrene sulfonate, sevelamer, and BASs) (Tables 1 through 3). The authors collate the findings of published literature, importantly including recently published research papers, and authors' personal experiences from clinical sign-out and consult cases. We also recognize that the list of unidentified and hence unknown iatrogenic agents manifesting as foreign material in the GI tract may be longer than the list of known and published agents. As we continue to recognize these newer agents, this list continues to evolve. Older, widely recognized drugs presenting as foreign materials, such as calcium and iron, are not discussed in this review, nor are drugs causing GI tract injury without associated foreign material in the retrieved specimens (such as nonsteroidal anti-inflammatory drugs, proton pump inhibitors, doxycycline, taxanes, olmesartan, and many others).
Pharmaceutical fillers, such as crospovidone and MCC, are inactive substances integrated into consumables to facilitate their delivery. Both are insoluble, nonabsorbable white powders.7,23 They are incorporated into many over-the-counter and prescription medications, such as omeprazole, oxycodone, acetaminophen, and alprazolam, as well as vitamins and processed food products7,23,24 (Table 1). Although well recognized in the pulmonary pathology literature,25–27 the histologic features of crospovidone and MCC have only recently been recognized in the GI pathology literature.7,28 They are often seen together and have been identified in between 0.3% and 9.0% of GI surgical specimens.7,28
Although both crospovidone and MCC can be identified in any part of the tubular GI tract, they have most commonly been identified in the small bowel.7 On hematoxylin-eosin (H&E) staining, crospovidone has a coral or sponge shape with each segment composed of a pink center and purple coat and a size range of 0.4 to 1.5 mm in diameter7,28 (Figure 1, A). Crospovidone is nonbirefringent under polarized light (Figure 1, B). On H&E, MCC has a rod or matchstick shape, is transparent, ranges in size from 1 to 2.0 mm in diameter, and is brightly birefringent under polarized light7 (Figure 1, A and B). Interestingly, the precise architecture of histologically processed crospovidone can vary by medication: histologically processed pharmaceutical-grade crospovidone shows the usual coral architecture, but that derived from omeprazole has a more linear arrangement, and that derived from oxycodone has a smaller, more crumbled appearance (Figure 2, A through C). Because these subtle architectural changes have not been well studied, ascribing a particular pattern of crospovidone to a particular medication should be avoided. Notably, when crospovidone is identified in a background of ulcer, inflammation, or ischemia, it can display an altered appearance with a diminished purple coat and a more uniformly yellow or brown color (Figure 3). This likely could be due to the effects of tissue reaction or degradation in damaged backgrounds or differing microenvironments secondary to tissue necrosis and altered pH.7 In these cases, crospovidone retains its characteristic coral shape, and this serves as a helpful diagnostic clue7 (Figure 3). This is in contrast to crospovidone in the lungs, which exhibits a solid blue or black color on H&E.25,26 The altered morphologic appearance described above in the GI tract has not been described in pulmonary pathology literature. Crospovidone and MCC are easily identified on H&E (Figure 1, A). Their histochemical profiles are detailed in Tables 2 and 3.7
Awareness of the histopathologic features of pharmaceutical fillers is helpful to distinguish them from their morphologic mimics. Crospovidone is distinguished from calcifications via a von Kossa stain, which stains calcium black, crospovidone dark orange, and MCC light pink. Although both MCC and talc are colorless on H&E and brightly birefringent, talc has a much smaller size, varying from 0.1 to 100 μm (typically between 0.3 and 50 μm),29 a square shape, and a stacked-plate appearance, and remains colorless on periodic acid–Schiff (PAS), Congo red, and Grocott methenamine silver (MCC is light purple on PAS, light salmon on Congo red, and brown-black on Grocott methenamine silver; Table 3).27
Crospovidone and MCC are common, and the published data support that they are not associated with mucosal injury in the GI tract7 (Table 1). Accordingly, we generally do not include these agents in the formal pathology report. However, their presence outside of the luminal GI tract may serve as a surrogate marker for perforation, as the fillers are designed for oral administration and are nonabsorbable. In contrast, the presence of crospovidone and/or MCC in the lung is always abnormal and secondary to intravenous drug abuse or aspiration.25,26 Ganesan et al25 reported the association of fillers with pulmonary angiothrombosis, foreign body granulomatous reaction, and granulomatous angiitis. Mukhopadhyay and Katzenstein26 reported MCC in 12% and crospovidone in 7% of 59 cases of aspiration pneumonia. The pulmonary pathology identified included bronchiolitis obliterans organizing pneumonia, suppurative granulomata, foreign body giant cell reaction, and/or acute inflammation. The association of fillers with thrombotic granulomata has been implicated as a contributor to vascular sclerosis with subsequent development of pulmonary hypertension and cor pulmonale.30–32
SUBMUCOSAL LIFTING AGENTS
Eleview and ORISE are recently introduced synthetic lifting agents. They are injected into the submucosa during an endoscopic procedure to fully visualize and resect flat or sessile lesions5,33–36 (Figure 4, A and B). They are most commonly seen in the resection of sessile colonic polyps, but can also be used for removal of sessile lesions in the esophagus, stomach, and small bowel (Table 1). Eleview was the first approved, in 2017, and is a solution containing water, sodium chloride, poloxamer 188 (a bulking and structuring agent), polyoxyl-15-hydroxystearate (an emulsifier), methylene blue (a contrast and staining agent), and medium-chain triglycerides (an oil component).34,36 ORISE was subsequently approved in 2018 and has a similar composition but a more gelatinous texture.34 Compared with the more traditional agents composed of saline and methylene blue, these new submucosal lifting agents are more expensive, but they offer the advantage of immediate availability without requiring media preparation during the procedure.5,34,36–38 Compared with the more traditional agents, studies have shown that these newer submucosal lifting agents are equally safe, are more effective, require fewer repeat injections, and have a decreased procedure duration because they maintain the submucosal fluid cushion for a longer period of time.33,37,38
ORISE and Eleview have a similar histologic appearance.5,35,36 These agents are best seen in the submucosa, and the morphology changes with time. Immediately after injection, the agent has a similar appearance to acellular mucin on H&E and manifests as extracellular pale, blue-gray, amorphous, and variably bubbly to finely granular material (Figure 4, C and D). At this stage, the agent has been variably reported to be mucicarmine reactive by some authors36 and nonreactive to mucicarmine in other studies.39 The agent is nonreactive for PAS and Alcian blue (Tables 2 and 3). Resection a day after lifting agent injection shows a less bubbly but more solid appearance with infiltrating neutrophils. Resection 2 to 3 months after lifting agent injection grossly presents as a white-tan, firm submucosal mass. Histologic sections show prominent amorphous, pink hyaline-like material with a foreign body giant cell reaction and fibrosis, also referred to as lifting agent granuloma5,35,36,39 (Table 2; Figure 4, E and F). The hyalinized ribbons and globules seen in the older lesions are thought to represent degrading lifting agent or a tissue reaction to the degrading agent.5 The material and its resultant reaction can extend into the muscularis propria, or even the subserosa, and can clinically simulate a transmural neoplasm. At this stage, the material is no longer mucicarmine reactive. However, it demonstrates a light blue on trichrome and Alcian blue pH 2.5, pink on PAS and PAS-diastase, and blue-purple on acid-fast bacilli, and is reported to be nonreactive for Congo red, Movat, mucicarmine, Grocott methenamine silver, colloidal iron, and von Kossa (Table 3). This material is neither refractile nor polarizable.5,35,36 It has been proposed that (at a minimum) submucosa is required to trap and stabilize the lifting agent so that it survives histologic processing, as the lifting agent is not identified in cases containing mucosa alone, even if the endoscopist specifically biopsied the lifting agent.5
The age of the lifting agent lesion gives rise to specific diagnostic pitfalls that are largely dependent upon the time frame of the excision after injection.5,35,36 The mucinlike appearance (Figure 4, C and D) seen immediately after injection is histologically similar to that of malignant mucin pools. Most cases will not pose a diagnostic challenge with the presence of neoplastic cells supportive of neoplastic mucin in the malignant mucin pools (Figure 5, A). In challenging cases, neoplastic mucin shows strong reactivity with Alcian blue, in contrast to faint Alcian blue staining seen with the lifting agent.36 In this phase of the lesion, one author received a consultation case submitted with a concern for mucosal/submucosal myxoma. Familiarity with the spectra of typical lifting agent histology and chart confirmation of use of a submucosal lifting agent are reassuring.
The more hyalinized form of the lifting agent seen months postinjection (Figure 4, E and F) can simulate amyloid (Figure 5, B) or a pulse granuloma (Figure 5, C and D). In contrast to submucosal lifting agents, amyloid deposits involve vessels and are Congo red reactive with an apple green birefringence when polarized (Figure 5, B). The aged deposits of submucosal lifting agents also show morphologic similarity with pulse granulomata. Pulse (or hyaline ring) granulomata represent a granulomatous response to partially digested food (vegetables or legumes) introduced through mucosal disruption of some sort, such as diverticular disease, perforation, ostomy-site changes, fistulas, appendicitis, and malignancy-related disruption, among others.40 Overlapping histologic features include extracellular deposits of dense, eosinophilic hyaline rings or ribbons that do not involve vessels and that are Congo red nonreactive.5,35,36,40–42 Helpful features supporting a diagnosis of pulse granulomata include a history of mucosal disruption, background variably sized heterogeneous mineralization and entrapped food, and lack of a history of lifting agent injection.40–42
It is important to be aware of the varied histologic appearance of newly described submucosal lifting agents to avoid the diagnostic mimics of mucinous neoplasms, amyloid, and pulse granulomata to prevent unnecessary additional costly studies and patient anxiety (Table 1). In most cases, the diagnosis can be rendered on H&E alone, assuming the characteristic histology is present and there is a supporting history of lifting agent injection.
Introduced in the United States in 2005, lanthanum carbonate (Fosrenol, Shire Pharmaceuticals) treats hyperphosphatemia in patients with end-stage renal disease43–48 (Table 1). Patients with chronic renal failure have a diminished ability to remove phosphorus from the bloodstream, resulting in hyperphosphatemia. Persistent hyperphosphatemia results in osteoporosis and deposition of calcium phosphate in the blood vessel walls, leading to arteriosclerosis and an increased risk of cardiovascular events and mortality. After intake of lanthanum carbonate, the lanthanum ion released in the stomach combines with dietary phosphate in the intestinal tract. The majority of the lanthanum phosphate is an insoluble complex that is excreted from the body in the feces, thereby depleting the body of phosphate. Lanthanum carbonate absorption in the gastroduodenal mucosa is postulated to occur directly through the gastroduodenal epithelium.49,50
Gross and Endoscopic Examination
Recent reports indicate that lanthanum can deposit throughout the GI tract mucosa, most commonly in the stomach, but also in the small intestine and colon. Rare reports include deposition in a tubular adenoma of the transverse colon, mesenteric lymph nodes, and gastric regional lymph nodes. The prevalence of gastric lanthanum deposition in end-stage renal disease patients on lanthanum carbonate therapy has been reported to be 60% to 85%.46,51,52 However, these studies are largely retrospective, with sampling biases that likely account for the relatively uncommon incidence of lanthanum carbonate in routine pathology practice. The endoscopic features of lanthanum carbonate are variable and can be discreet or diffuse: small polyps, erosions, slightly depressed lesions, or red or white mucosal irregularities; they can also be endoscopically unremarkable49,50,53 (Figure 6, A). The deposition can be detected years after cessation of therapy.46,49,50,53
A diagnosis of lanthanum deposition can be made on H&E with confirmation from the medication list. Histologic sections show prominent histiocytic infiltration with fine, amorphous deposits in the cytoplasm (Figure 6, B through D). The histiocytes are most prominent in the superficial mucosa, where they can form aggregates separating and splaying the glands in the mucosa. This deposited material is variably described as eosinophilic; elongated; inclusion-like with complicated branching, coiled, or crescentlike configurations; coarse granular brown or colorless material; amphophilic; and/or yellowish brown fine granules45,46 (Table 2). The colorless granular material is more easily perceptible in negative controls of immunostained preparations.45,49 The deposition accumulates in damaged gastric mucosa with regenerative changes, intestinal metaplasia, and foveolar hyperplasia.46,49 Although we do not grade the degree of deposition, some propose semiquantitative grading: grade 0, no deposition; grade 1, deposition in a very limited area of the biopsied material; grade 2, deposition in less than half of the area or in multifocal limited areas of the biopsied material; and grade 3, deposition in more than half of the area of the biopsied material.49
The lesional histiocytes are CD68 and CD206 reactive, suggesting that M2 macrophages are involved in the clearance of lanthanum from the gastroduodenal mucosa.54 Their MIB-1 labeling index is low (<1%). A Ziehl-Neelsen stain is negative for acid-fast bacilli, and the histiocytes show variable Prussian blue staining (Figure 6, E; Table 3). Scanning electron microscopic examination, x-ray diffraction, and elemental analysis have identified the granular cytoplasmic staining as lanthanum and phosphorus45,49 (Figure 6, F). In scanning electron microscopy, lanthanum deposition is seen as bright areas composed of aggregates of particles measuring 0.5 to 3 μm in diameter.46,50
The lamina propria histiocytic accumulation raises a differential diagnosis of epithelioid granulomatous diseases such as tuberculosis and sarcoidosis. However, lanthanum deposition does not feature granulomata, and special stains for acid-fast bacilli are negative. Gastric calcinosis and iron-induced mucosal injury are also in the differential diagnosis. Mucosal calcinosis is characterized by the presence of superficial and extracellular coarse black-purple pigment, which is confirmed by a von Kossa special stain (lanthanum deposits are von Kossa negative). Mucosal calcinosis is important to recognize because it may serve as an indicator for generalized metastatic calcification, especially in organs where it may be fatal, such as the heart; hence, it is important to avoid misdiagnosis of mucosal calcinosis as lanthanum.55,56 Distinction of lanthanum from iron deposition with a Prussian blue special stain can be tricky, as both can be reactive, but lanthanum deposition is usually focal and subtle57,58 (Figure 6, E).
Granular cell tumor and crystal-storing histiocytosis are also in the differential diagnosis. Granular cell tumor typically consists of a proliferation of sheets and nests of polygonal to fusiform cells with abundant eosinophilic to amphophilic granular cytoplasm and small nuclei with only occasional nucleoli. Granular cell tumors are positive for S100 and SOX10, and retain PAS staining after diastase digestion. Unlike lanthanum, crystal-storing histiocytosis features a prominent histiocytic infiltrate with abundant nonrefractile, nonpolarizable, fibrillary cytoplasmic inclusions59–64 (Figure 7, A through C). Crystal-storing histiocytosis is highly associated with a hematolymphoid malignancy, inflammatory diseases, and specific medications, such as chronic clofazimine for leprosy treatment. In our centers, identification of crystal-storing histiocytosis triggers a careful hematopathology review with at least CD3 and CD20 immunostains. If that workup is negative and the patient lacks pertinent risk factors (leprosy, for example), we suggest additional studies based on the high risk for an (unsampled) hematolymphoid malignancy: imaging studies to evaluate for lymphadenopathy, hepatosplenomegaly, or additional masses; complete peripheral blood count; serum and urine protein electrophoresis; and bone marrow biopsy.59
The pathologic significance of lanthanum deposition in the GI mucosa has not been elucidated, and there is no agreement if patients with histologic lanthanum deposition should cease lanthanum administration. At a minimum, some have suggested such patients undergo endoscopic surveillance to monitor disease progression.46 Identification of lanthanum also serves as a helpful prompt to consider other diagnoses associated with renal failure (amyloid, cytomegalovirus, etc) (Table 1).
Polymers are commonly used as surface coatings on endovascular devices. The hydrophilic polymers absorb water, thereby enhancing device lubrication and manipulation and reducing complications such as endothelial damage, vascular spasm, and thrombosis. Of note, polymer coatings have the potential to induce significant adverse reactions, including unanticipated dissociation of polymer particles from device surfaces and resultant downstream thromboembolic events. Diverse complications can be seen depending upon the site of involvement, such as stroke, myocardial infarction, pulmonary infarctions, pulmonary embolism, limb ischemia, skin or soft tissue damage, and recently reported polymer-associated ischemic enterocolitis3,65–68 (Table 1).
All cases of polymer-associated ischemic enterocolitis reported thus far have a documented history of a recent endovascular procedure, with the majority having a recent history of aortic aneurysm repair.3 Most patients present with clinical signs and symptoms of bowel ischemia. The reported 19% incidence of hydrophilic polymer–associated enterocolitis among all cases of aortic repair–associated ischemic enterocolitis is likely an underestimate, because not all such patients proceed to surgical resection or autopsy.69 A retrospective review of 136 hospital autopsies reported a 13% hydrophilic polymer incidence rate, with polymers identified in the lungs, heart, and central nervous system.68
Histologically, the resected small bowel and colon show extensive ischemia. The hydrophilic polymers are seen only in areas of ischemia and are located mainly in the submucosal vessels (Figure 8, A). On H&E, the hydrophilic polymers appear as intravascular, serpiginous structures with stippled basophilia and are identical to those described in hydrophilic polymers involving other sites3,65,67,68,70 (Figure 8, B and C). The polymers are nonrefractile and nonpolarizable.
The polymers can be seen in tissues at least 3 months after the aortic repair, and their morphology changes over time. A resection specimen taken later in the time course shows partially degrading polymers with diminished polymer numbers that appear less basophilic, more amorphous, and mostly associated with a foreign body giant cell reaction. Because the polymers are usually restricted to the submucosa, they are unlikely to be sampled in superficial mucosal biopsies. Ancillary stains can be used when in doubt; the polymers appear turquoise on colloidal iron, pink on von Kossa and mucicarmine, and pale blue on trichrome3 (Tables 2 and 3).
The hydrophilic polymers are occasionally mistaken for parasites, given their serpiginous appearance. Features supporting a diagnosis of polymers include their lack of a well-defined cuticle, internal structures, eosinophilia in the surrounding tissues, and the presence of associated ischemia in a patient with a recent history of endovascular manipulation. In the later stages, the presence of a foreign body giant cell reaction can sometimes raise the possibility of systemic granulomatous processes; however, the awareness of the polymer's morphologic appearance over time and correlation with clinical history is helpful.
Given that the polymers are identified exclusively in areas of ischemia, the polymers likely cause the ischemic injury, similar to their mechanism of ischemia described in other sites.65,67,70–73 Awareness of their morphology and direct communication with the clinician can be important to ensure that the patient is carefully monitored for additional polymer-associated ischemic events (Table 1).
OsmoPrep (sodium phosphate monobasic monohydrate and sodium phosphate dibasic anhydrous) is a tablet form of bowel preparation approved in the United States in 2006.74 The active ingredient is sodium phosphate, and it functions as an osmotic laxative. The prescribing frequency of OsmoPrep is low because of the associated risk of acute phosphate nephropathy and the strenuous prescribing instructions: a required consumption of a large volume of clear liquids on the evening and morning before the endoscopic procedure in conjunction with multiple large OsmoPrep tablets. In addition, because a concurrent upper endoscopy is not uniformly performed in all patients using OsmoPrep, the true incidence of OsmoPrep-associated injury remains unknown.74
The first report of histologic evidence of OsmoPrep-associated gastritis was published in 2016.74
Histologic sections from the involved gastric biopsies show a reactive gastropathy pattern of injury characterized by marked reactive epithelial change, prominent mucin loss, and nuclear hyperchromasia. Mild superficial edema and congestion may be present. These changes are associated with brown to black mineralization in the superficial lamina propria. The material has been described as similar to crushed pill fragments, which are generally less than 100 μm in greatest dimension74 (Figure 9, A and B). They can have a smooth, almost translucent appearance or a more opaque and granular appearance (Table 2). The deposits are most frequently identified in the antrum. To date, these agents have not been linked with histologic evidence of deposits in other GI organs.74
These deposits are von Kossa stain reactive and are nonreactive on alizarin red, a calcium chelating dye, and Perls iron stain (Table 3). The von Kossa reactivity is a false-positive that represents a chemical reaction of the phosphate or carbonate moiety of the calcium salt, and not calcium itself, as supported by nonreactivity with alizarin red, a dye that directly binds calcium.74
Although neither major complication nor specific therapeutic intervention has been reported,74 correct identification can prevent the diagnostic pitfall of iron or mucosal calcinosis.
Selective internal radiation therapy uses 90Y-labeled microspheres to deliver radioactive microspheres through the hepatic artery directly to the neoplasm in patients with unresectable neoplasms in the liver.10,75–77 Yttrium 90 is a pure β emitter with a short half-life (2.67 days) and decays to zirconium 90.1,78 This targeted therapy allows directed delivery of high radiation doses to the neoplasm, leading to significant tumoricidal effect while diminishing damage to the adjoining nonneoplastic tissue. This mechanism relies on the differential blood supply of the neoplasm and the adjacent nonneoplastic liver: whereas malignant neoplasms in the liver derive at least 95% of their blood supply from the hepatic artery, the majority of the blood supply of the normal liver is from the portal vein.79,80
The safety and efficacy of selective internal radiation therapy in the treatment of primary and metastatic liver malignancies has been demonstrated by a number of groups. Yttrium 90 therapy has shown promising rates of complete pathologic response in patients prior to hepatic resection or transplantation (89% for smaller neoplasms and 65% for larger neoplasms).81 Yttrium 90 radioembolization has also been shown to significantly prolong the time to disease progression when compared with conventional transarterial chemoembolization in a phase 2 study of hepatocellular carcinoma.82
However, a known complication of 90Y therapy is inadvertent extrahepatic embolization of radioactive microspheres, leading to extrahepatic radiation-induced tissue injury, which is more severe than that typically seen with lower dose external-beam radiotherapy.10,83–85
There are 2 different preparations of microspheres for selective internal radiation therapy approved by the US Food and Drug Administration: TheraSphere and SIR-Sphere.1,78 TheraSphere was approved in 1999 to treat unresectable hepatocellular carcinoma and SIR-Sphere was approved in 2002 to treat metastatic colorectal carcinoma to the liver,1 although institution-specific practices take priority over cancer subtype in determining which 90Y is used in some centers1 (Table 1).
TheraSphere microspheres are glass microspheres 20 to 30 μm in diameter that emit 2500 Bq of radioactivity per sphere. In contrast, SIR-Sphere microspheres are resin microspheres, are larger (20–60 μm), and emit less radiation (50 Bq per sphere). 1,11,85 Because SIR-Sphere has a 50 times lower radiation dose, a greater dose of SIR-Sphere (up to 30 million particles per treatment) is needed to achieve the same radiation effect as TheraSphere (about 1.2–8 million particles per treatment).1,85,86 In addition, SIR-Sphere's larger size has been implicated in impeding full dose delivery and exceeding the arterial vascular capacity, thereby leading to enhanced risk of arterial vascular stasis and accompanying reflux into and embolization of nontarget places.11,87,88 As a result, some suggest that TheraSphere provides clinical advantages over SIR-Sphere, although these reports contain industry associations.11,87,88
Gastroduodenal complications such as ulceration, gastritis, and duodenitis are the most commonly reported, but other complications can include cholecystitis, pancreatitis, radiation hepatitis, radiation pneumonitis, pulmonary fibrosis, bone marrow toxicity, and veno-occlusive disease.1,10,75,85,87,89,90 The incidence of gastric ulceration is 3% to 29% in patients receiving whole-liver selective internal radiation therapy,10,76,85 and 90Y-induced gastroduodenitis can be seen as soon as 10 days and up to 5 months after treatment.76
Histopathologic sections from SIR-Sphere show round, deep purple to black foreign bodies measuring from 20 to 60 μm in mucosal vessels and in extravascular locations, may show shattering artifact on histologic sections, and may be confused for psammoma bodies1,10,76 (Figure 10, A and B). TheraSpheres are colorless, refractile, polarizable, and 20 to 30 μm in diameter, and occasionally contain an internal bull's-eye with the condenser out and an internal cross with polarized light1 (Figure 10, C and D). Because the size of TheraSphere overlaps with that of SIR-Sphere, color is a better discriminating feature than size in diagnosing these microspheres. TheraSphere is more difficult to recognize than SIR-Sphere based on its relatively smaller size, colorless appearance, sparse distribution, and less striking background radiation injury. This likely accounts for TheraSphere only recently having been described in the pathology literature in 2019, despite its approval for use in the United States before SIR-Sphere was approved in 2002.
The background mucosa can show a wide spectrum of changes owing to the radiation-induced injury involving both epithelial and stromal cells, including nuclear and cytoplasmic enlargement, nuclear hyperchromasia, sometimes bizarre shapes, reactive changes, lamina propria hyalinization, and variable ischemic injury, erosions, and ulceration. In some cases, an associated granulomatous and fibrous reaction in the lamina propria can be seen. The vessels can show necrosis of their walls, capillary ectasia, prominent plump endothelial cells, and/or fibrous intimal thickening76 (Table 2). SIR-Sphere has been reported in the stomach, duodenum, gallbladder, and pancreas. TheraSphere has predominantly been identified in hepatectomy specimens, but it has also been reported in the stomach and gallbladder in the small series available.1,11
The radiation-associated regenerative stromal and epithelial atypia can be striking and should not be mistaken for a malignancy (Table 1). Recognition of characteristic microspheres and the clinical history is reassuring.
SIR-Sphere can also be confused for psammoma bodies or other calcospherites. Similar to SIR-Sphere, psammoma bodies are deep purple and may show shattering artifact on H&E, and misidentification as such could lead to a misdiagnosis or patient anxiety for a neoplasm with psammoma bodies. Features favoring psammoma bodies include concentric laminations, a wider size variation, an associated neoplasm, and absence of background radiation injury (Figure 10, B). To those unfamiliar with TheraSphere, it would be easy to dismiss the microsphere as an air bubble. Unlike air bubbles, however, TheraSphere cannot be pushed off the glass slide by pressure applied to the coverslip, and TheraSphere often contains a bull's-eye with an internal cross seen under polarized light, features not seen with air bubbles.1
Recognition of microspheres is important because these patients all have a history of malignancy, and this finding can help establish the cause of the background inflammatory or radiation-related injury. Importantly, the striking radiation-induced atypia should not be misdiagnosed as a malignant neoplasm (Table 1).
Resins are nonabsorbable drugs that serve as medias for ion exchange in the GI tract.4,9 They are typically ingested and their crystal forms are almost always identified along the tubular GI tract. In cases of stent manipulation, fistula formation, or aspiration, however, they can escape the tubular GI tract and be seen in unusual locations, such as the gallbladder, necrotic pancreas, ostomy resection specimens, or lung.4,26
To date, 3 types of resins have been identified: sevelamer, sodium polystyrene sulfonate (Kayexalate, Concordia International Corp, Oakville, Ontario, Canada), and BASs. Sevelamer (Renvela and Renagel, Sanofi SA, Paris, France) was the latest described in 2013 and is an anion-exchange resin used to treat hyperphosphatemia in patients with chronic renal disease91 (Table 1). Sevelamer is often misdiagnosed as sodium polystyrene sulfonate (Kayexalate) because of similar patient characteristics of end-stage renal failure and both resins classically featuring “fish scales,” or internal demarcations that appear similar to the surface of a fish (Figure 11, A and B). Lastly, the BAS family includes 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). The various BAS resins are histologically indistinguishable from each other and are best diagnosed as BASs. A specific diagnosis as colesevelam, colestipol, or cholestyramine necessitates corroboration with the patient's medication list.
Bile acid sequestrants were initially introduced to treat hypercholesterolemia. They form an insoluble complex with bile acids in the GI tract lumen, causing their removal into the feces and diminishing the endogenous reservoir of bile acids. As a result, the hepatobiliary system compensates by synthesizing more bile acids from cholesterol precursors, thereby decreasing serum cholesterol levels. Today, the most common indication for BAS is diarrhea, with the easier-to-tolerate statins now representing the medication of choice to treat hypercholesterolemia2 (Table 1). Additional applications of BAS include the treatment of bile acid–mediated diarrhea and bile acid–mediated pruritus, and better glycemic control in adults with type 2 diabetes mellitus.2,4,9
Typically, all resins are polygonal or rectangular. Sodium polystyrene sulfonate is purple on H&E and shows a fish-scale appearance4,8,9 (Figure 11, A). Sevelamer is usually 2-toned in color on H&E, consisting of bright pink linear accentuations with a rusty yellow background, and, like sodium polystyrene sulfonate, also features fish scales (Figure 11, B). Bile acid sequestrants are usually bright orange on H&E with a smooth or glassy texture that lacks fish scales (Figure 11, C). They can occasionally feature minute, pink, dotlike inclusions4 (Table 2).
Resins are notorious for displaying atypical morphology, as extensively discussed by Gonzalez et al,4 and these can pose diagnostic challenges. Although classically the resins are described as polygonal or rectangular in shape, they can occasionally present as rounded structures, as reported for colestipol.92 Additionally, fish scales are nonspecific and can be seen even with dystrophic calcifications, unspecified luminal contents (likely food), and large BAS fragments. Moreover, smaller sodium polystyrene sulfonate crystals may lack a fish-scale appearance. The shape of the fish scales is not specific to a specific resin. Sodium polystyrene sulfonate, sevelamer, and BASs can all have broad or narrow fish scales, although fish scales in BASs are rare and almost always seen with large resins or thick sections, likely as a result of processing artifact. A helpful diagnostic pearl is that the characteristic BAS morphology is usually seen in the smaller BAS fragments.
The H&E color of sevelamer and BASs can vary considerably, and this adds diagnostic difficulty. Bile acid sequestrants can appear black, deep red, or dull orange in color, and consequently overlap in color with sevelamer. Sevelamer crystals can show an altered, variably appearing, deeply eosinophilic,4 or rusty brown color when embedded in damaged (ulcerated or ischemic) mucosa or necrotic debris, although they typically retain their fish scales.
Knowledge of the characteristic resin morphology and common diagnostic pitfalls facilitates the majority of resins diagnosed on H&E alone, with chart confirmation offering the most useful confirmatory study. If the chart is not available, the acid-fast bacillus special stain is the most consistent discriminatory tool: it stains BAS dull yellow, sodium polystyrene sulfonate black, and sevelamer magenta4,9 (Table 3).
Confidence in discriminating between these resins is essential because sevelamer and sodium polystyrene sulfonate can be associated with GI tract injury and BASs are biologically inert (Table 1). Sodium polystyrene sulfonate has been linked to severe injury, including bowel ischemia, ulcerations, necrosis, pseudotumors, and perforations. This was historically attributed to its hyperosmotic sorbitol diluent and not the resins themselves. However, some investigators found that even oral administration of the sodium polystyrene sulfonate powder alone, without the diluent, can result in similar injuries, suggesting that the resins themselves may directly inflict GI tract injury in a subset of patients.12,16,20,93 Sevelamer has also been associated with mucosal injury by multiple investigators, sometimes in a dose-dependent manner, suggesting it also may have the potential to cause significant injury in some patients.8,94–96 Sodium polystyrene sulfonate– and sevelamer-associated mucosal injuries necessitate immediate clinician contact to ensure close patient monitoring or medication adjustments.
Of note, sodium polystyrene sulfonate and sevelamer do not cause injury in all cases; otherwise, they would not be on the market. In our experience, the majority of cases of sodium polystyrene sulfonate and sevelamer are not associated with injury. They seem to be associated with injury in cases where there is underlying bowel injury, such as amyloidosis, gastroparesis, or severe constipation. Perhaps these particular patients are more vulnerable to sodium polystyrene sulfonate and sevelamer injury because the resins have extended contact time with the mucosa secondary to delayed bowel motility.
Resins are also important to recognize because they can serve as clues to other important diagnoses. For example, sodium polystyrene sulfonate and sevelamer are used in the setting of renal failure and should serve as prompts to look for other diagnoses associated with renal failure, in particular amyloidosis, mycophenolate, lanthanum, mucosal calcinosis, and opportunistic infections, such as cytomegalovirus. Similarly, the most common indication of BAS is diarrhea, and its recognition should prompt consideration of causes of diarrhea, such as cytomegalovirus, amyloid, and mycophenolate, among others.
Awareness and recognition of these newer foreign materials is important for correct diagnosis, optimal patient care, and avoiding additional unwarranted workup. Although this review aims to serve as a helpful guide for the latest iatrogenic foreign material seen in the GI tract, the authors realize that the list of unknown agents is much longer than this list of known agents. While the unknown agents slowly transform into known entities, careful scrutiny of the tissue may prove most helpful as the dazzling world of idiopathic agents continues to unfold.
The authors thank Lisa Litzenberger (Department of Pathology, University of Colorado Anschutz Medical Campus) for her assistance with the photomicrographs. The OsmoPrep glass slide is courtesy of Klaudia M. Nowak, MD, FRCPC (Laboratory Medicine Program, University Health Network, Toronto, Canada).
The authors have no relevant financial interest in the products or companies described in this article.