Rare non-neoplastic gastrointestinal diseases–drugs and bugs

The clinical presentation of nonsteroidal anti-inflammatory drug (NSAID)-induced injury is often nonspecific, ranging from iron-deficiency anemia due to occult blood loss to symptoms of subacute small bowel obstruction in cases of chronic stricture formation, also known as “diaphragm disease.” A critical clinical feature is the poor correlation between upper GI symptoms and the presence of significant mucosal damage. Severe life-threatening complications like bleeding or perforation can occur without any prior warning symptoms. While NSAIDs can damage the entire gastrointestinal tract, the histopathologic findings vary by location. Due to the formulation of most modern medications, including NSAIDs, leading to release of the active components in the stomach or further along the intestinal tract, NSAID-induced damage in the esophagus is rare. In the stomach—the primary site of NSAID-induced damage—inhibition of prostaglandin synthesis by inhibition of cyclo-oxygenase is the driving force behind NSAID-induced injury. While NSAIDs classically cause ulceration of the stomach mucosa due to the missing protective effect of prostaglandins, a reactive gastropathy defined by foveolar hyperplasia with a characteristic corkscrew appearance, mucosal edema, and fibromuscular hyperplasia of the lamina propria, all with a notable paucity of inflammatory cells, may also be the only NSAID-associated damage present [8].

In the small intestine, NSAIDs mostly cause unspecific ulceration and erosion; however, a rare but significant complication of long-term NSAID use is diaphragm disease, characterized by thin, concentric septa that cause stenosis. Histologically, these diaphragms consist of a core of submucosal fibrosis admixed with disorganized smooth muscle, unmyelinated nerve bundles, and angiomatous blood vessels. In the large intestine, NSAID-associated injury typically manifests as nonspecific, patchy inflammation, in some cases with erosion and ulceration, predominantly in the right colon. The inflammatory infiltrate is variable and can be mixed lymphoplasmacytic and neutrophilic, predominantly neutrophilic (mimicking infectious colitis), or predominantly lymphocytic. While mild crypt architectural disarray is common, features of established chronicity like significant crypt distortion (branching, atrophy) or prominent basal plasmacytosis can be absent [9, 10].

The differential diagnosis of NSAID-induced enterocolitis primarily includes Crohn’s disease (CD), ischemic colitis, and infectious colitis. Unlike CD, NSAID injury lacks granulomas, transmural inflammation, and deep fissuring ulcers. Histologically, NSAID-induced inflammation is typically less severe, with a milder lymphoplasmacytic infiltrate and less architectural distortion than in active CD. NSAIDs can also induce an ischemic-type colitis, although the inflammation in NSAID colitis seems to be generally milder than that seen in primary ischemic colitis. The acute neutrophilic pattern can be histologically indistinguishable from infectious colitis, making the exclusion of pathogens via clinical and microbiologic studies essential for diagnosis [10, 11].

Colchicine and taxanes interfere with microtubule function, leading to mitotic arrest [12, 13]. Clinically, this manifests as nausea, vomiting, abdominal pain, and diarrhea for both drug classes. For patients taking colchicine, these gastrointestinal symptoms are the earliest and most frequent manifestations of toxicity, which can be severe and even fatal, particularly in those with renal or hepatic impairment. For patients on taxane-based chemotherapy (e.g., docetaxel or paclitaxel), similar GI side effects are common but are generally considered part of the expected cytotoxic effects of the treatment. The histopathologic effects are strikingly similar for both drug classes and are characteristically confined to the proliferative compartments of the epithelium, such as the crypts, while sparing the mature, differentiated surface epithelium. The hallmark histologic features include a marked increase in apoptosis within the crypts and accumulation of epithelial cells arrested in metaphase. Many of these arrested cells display a pathognomonic “ring mitosis,” where condensed chromosomes form a circular or wreath-like configuration. These changes can be accompanied by reactive epithelial atypia, including nuclear enlargement, pseudo-stratification, and a loss of normal nuclear polarity. The differential diagnosis is unique because the histologic findings for colchicine and taxanes are identical. The distinction is entirely clinical and dictates management: for a patient on colchicine, these findings are diagnostic of toxicity and require immediate drug cessation; for a patient on taxane-based chemotherapy, the same findings represent the intended therapeutic effect and may be seen in asymptomatic patients, not necessarily indicating toxicity. The reactive atypia can also mimic high-grade dysplasia. The crucial distinguishing feature is that the drug effect is sharply limited to the crypt bases, with preserved epithelial maturation toward the surface—a feature that is absent in true dysplasia, which is defined by the extension of atypical features to the surface epithelium [13].

The primary clinical symptom of ICI-induced colitis is diarrhea, which is often accompanied by abdominal pain and fever. The onset is typically delayed, with a median time of 6–8 weeks after initiation of anti-CTLA‑4 therapy and 3–6 months for anti-PD-1/PD-L1 agents. The condition can progress rapidly to severe complications like toxic megacolon or perforation if not treated [14]. Histopathologically, ICI-induced colitis is a great mimicker, presenting with a spectrum of overlapping injury patterns; the presence of multiple patterns within the same biopsy set is a strong clue to the diagnosis. The most common patterns include the following: an acute active colitis with neutrophilic cryptitis and crypt abscesses, resembling infectious colitis; a chronic active pattern with architectural distortion and basal plasmacytosis, mimicking inflammatory bowel disease (IBD); an apoptotic pattern with prominent crypt cell apoptosis, resembling graft-versus-host disease (GVHD); and patterns that are histologically identical to lymphocytic or collagenous colitis [15]. Given this histologic diversity, ICI-induced colitis is fundamentally a diagnosis of exclusion. The most critical differential diagnosis is infectious colitis, which must be ruled out by microbiologic studies before initiating immunosuppressive therapy. When differentiating from an IBD flare, the presence of prominent crypt apoptosis and less pronounced basal plasmacytosis strongly favors ICI colitis, whereas features like true granulomas or deep fissuring ulcers are diagnostic of Crohn’s disease. Compared to GVHD, the apoptotic pattern of ICI colitis is a close mimic but is typically accompanied by a more robust inflammatory infiltrate, whereas classic acute GVHD is characterized by a paucicellular lamina propria. Finally, while it can be histologically identical to idiopathic microscopic colitis, the ICI-induced form often has a more aggressive clinical course and may show overlapping features like cryptitis or apoptosis not typically seen in the idiopathic setting [8, 16].

Adsorbents and therapeutic resins, such as sodium polystyrene sulfonate (Kayexalate; used to treat hyperkalemia by binding intraluminal potassium) and sevelamer (a phosphate binder for hyperphosphatemia in chronic kidney disease), are nonabsorbable medications frequently encountered microscopically in gastrointestinal specimens. At high concentrations, these agents may cause mucosal injury, including ischemia, necrosis, stromal fibrosis, ulceration, and erosion with crystalline deposition. This can be detectable throughout the GI tract—with crystals occasionally seen in luminal exudate [4].

Kayexalate is associated with ischemia, mucosal necrosis, and potential perforation, although it can also be present without overt injury. Histologically, Kayexalate crystals are bright purple with a distinctive fish-scale pattern in H&E staining. Sevelamer can similarly cause GI mucosal injury; its crystals are yellow or pink, also displaying a fish-scale appearance. Other tablet fragments, including bile acid sequestrants, generally do not lead to mucosal damage but may be identified microscopically as pill fragments in tissue sections. Recognition of these characteristic crystalline or pill-residue findings is critical for accurate diagnosis and to avoid misinterpretation as primary pathologic processes [7, 16].

Giardia lamblia (syn. G. duodenalis, G. intestinalis) is a protozoan parasite causing an intestinal infection called giardiasis. It is one of the most common causes of waterborne nonviral and nonbacterial diarrheal disease, with over 300 million cases reported worldwide each year. In 2022 there were more than 10,000 confirmed cases of giardiasis in the European Union. The infection can be asymptomatic or associated with diarrhea, abdominal pain, malabsorption, and weight loss. There are high-risk groups including immunocompromised persons, infants, children, travelers visiting highly endemic regions, and individuals who practice unprotected oral/anal sex [17].

Giardia lamblia undergoes two primary stages in its lifecycle: the infectious cyst stage and the proliferative trophozoite stage. The infectious cyst is transmitted through the fecal–oral route, mainly by ingesting contaminated water or food containing cysts of Giardia. Transmission from person to person is also common, whereas animal-to-person transmission is less frequent.

Once the cysts reach the duodenum, they undergo excystation, releasing the trophozoites as the active form. This is stimulated by gastric acid and exposure to bile and pancreatic proteases. Symptoms occur during the trophozoite stage. The infection is mainly focused in the proximal small intestine. The trophozoites adhere to the microvilli of the enterocytes but remain noninvasive. Once dislodged, trophozoites pass through the small intestine and encyst upon reaching the colon. Excretion of cysts occurs through the feces.

Giardia trophozoites are pear-shaped and contain two nuclei. In profile they appear elliptical, resembling a “nail clipping,” and range in size from 10 to 20 μm in length. The infection causes villous atrophy and crypt hyperplasia in the small intestine. There is an increase in intraepithelial lymphocytosis and mild inflammation in the lamina propria. In most cases, however, the mucosa appears morphologically normal. Evaluation of the intervillous space is therefore a very important last look not to be missed by the pathologist when signing out duodenal biopsies [18].

Entamoeba histolytica is a protozoan parasite causing amebiasis. While 90% of E. histolytica infections remain asymptomatic, nearly 50 million people develop symptoms annually, resulting in up to 100,000 deaths each year. Infection is distributed worldwide, predominantly affecting areas with lower socioeconomic status and limited public health resources. Humans serve as the sole natural host. Transmission occurs primarily through fecal–oral contact via ingestion of food or water contaminated with cysts excreted in feces, while transmission through anal intercourse has also been documented.

The infection is typically located in the cecum and the rectum. Although most cases remain asymptomatic, amoebic colitis typically manifests with a subacute, gradual onset of watery or bloody diarrhea, loss of appetite, abdominal pain, and weight loss. In rare instances patients may progress to fulminant colitis, presenting with fever, severe hemorrhagic diarrhea, and clinical signs of peritonitis. This critical condition is associated with intestinal necrosis, perforation, and toxic megacolon and is linked to a high mortality rate. Liver abscess represents the most frequent extraintestinal manifestation and may develop months to years following exposure in endemic regions. In the gastrointestinal tract, the infection may mimic other gastrointestinal disorders, including inflammatory bowel disease, ischemic colitis, and various bacterial infections such as those caused by Clostridioides difficile, Shigella, Escherichia coli, Campylobacter, and Salmonella [1, 2].

The most frequent findings are flask-shaped ulcers or erosions in the lamina propria of mucosa. A limited breach of the mucosa is found accompanied by lateral extension into the submucosal layer. The mucosal surface is covered with inflammatory exudate composed of inflammatory cells, necrotic debris, and fibrin. Trophozoites are identified within this exudate. Edema and goblet cell depletion are also seen in the mucosal layer. Trophozoites display round to ovoid morphology, ranging from 6 to 40 μm in size. They exhibit pseudo-podial projections, small round nuclei, and a peripheral rim of condensed chromatin. The cytoplasm stains positive with periodic acid–Schiff (PAS) and demonstrates a granular appearance. They also may be difficult to distinguish from histiocytes, a problem which can be solved by immunohistochemical stains against histiocytic markers, e.g., CD68 [19, 20].

Schistosoma is a genus of trematode parasites responsible for chronic schistosomiasis, a disease predominantly affecting the intestinal tract and hepatosplenic system. The infection involves multiple other organ systems, including the spleen, central nervous system, and urogenital tract. Six primary species of Schistosoma are known to infect humans: Schistosoma japonicum, Schistosoma mansoni, Schistosoma haematobium, Schistosoma mekongi, Schistosoma interdental, and Schistosoma malayi [21]. The International Agency for Research on Cancer (IARC) classifies Schistosoma japonicum infection as possibly carcinogenic to humans due to its association with liver cancer, while the link between Schistosoma haematobium infection and bladder cancer is well established and recognized as carcinogenic.

Intestinal schistosomiasis refers to the acute and chronic inflammation of the intestines caused by Schistosoma infection, particularly by Schistosoma japonicum, Schistosoma mansoni, or Schistosoma mekongi, but typically not Schistosoma haematobium. Transmission occurs upon contact with freshwater containing snails which are the intermediate hosts. Cercariae, the infectious form of the parasite, penetrates human skin. The eggs subsequently migrate to the hepatic venules, where they mature into adult worms. Adult worms then migrate to the mesenteric veins of the intestines or the vesical venous plexus, where females deposit eggs that are ultimately excreted in the feces or urine.

Gastrointestinal schistosomiasis commonly affects the descending colon, sigmoid colon, and rectum. Most cases remain asymptomatic, while other cases manifest with fever, diarrhea, abdominal pain, bowel obstruction, and hematochezia. Clinically, it can resemble other gastrointestinal conditions, such as Crohn’s disease, acute viral and bacterial infections, and other parasitic helminth infections. Mass-forming inflammatory reactions may resemble polyps or cancer. Cases with severe pneumatosis have also been reported [22]. The infection is linked to significant morbidity and mortality, especially among populations with inadequate sanitation and limited access to safe drinking water.

Macroscopically, intestinal schistosomiasis typically presents with yellow, granular mucosa, and may also manifest as polypoid lesions. Ulcerations, edema, and hemorrhages can be observed. Histopathologic findings include submucosal fibrosis, acute and chronic inflammation, multinucleated giant cells containing Schistosoma eggs, and non-necrotizing granulomas. Of note, Schistosoma eggs are PAS negative but may react differently to Ziehl–Neelsen (ZN) staining (i.e., S. mansoni eggs are ZN negative and S. haematobium are ZN positive). During disease progression, eggs undergo calcification, which is accompanied by a progressive accumulation of fibrotic tissue in the affected areas [23].