—  SPECIALTY CONFERENCE  —

Surgical Pathology

Case 5 - SIR-Microsphere-Induced Gastroduodenal Ulcerations and Gastritis After SIRT

Gregory Y. Lauwers
Massachusetts General Hospital
Boston, MA





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Case History
The clinical history of this patient, a 63-year-old male, actually starts 12 months before the biopsy material available for review was sent to pathology. In the winter of 2007, this previously healthy male presented with 3 months history of rectal bleeding, abdominal cramping and weight loss. He was eventually diagnosed and operated for a 5 cm colonic adenocarcinoma (pT2N1M0). Adjuvant therapy was started using a combination of FOLFOX (5-fluorouracil, leucovorin, and oxaliplatin) and Avastin® (bevacizumab). However, 10 months post-operatively, he was diagnosed with multiple liver metastases involving both hepatic lobes for which he received FOLFIRI (5-fluorouracil, leucovorin, and irinotecan) and Avastin®. Interventional radiologic therapy was later attempted as well. Subsequently, the patient complained of belching, heartburn, and nausea. Eventually, after the symptoms waxed and waned for 2 months, an upper endoscopy was performed and demonstrated a diffusely erythematous and friable duodenal and gastric antral mucosa. Biopsies were performed.


Case 5 - Slide 1
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Case 5 - Figure 1
Endoscopic picture: the mucosa is diffusely erythematous.
Case 5 - Figure 2
The eroded mucosa displays moderate expansion of the lamina propria by mixed inflammatory infiltrate. The loss of glandular elements with withering epithelial elements is obvious.
Case 5 - Figure 3
Residual basal glandular elements with atypical epithelial cells are observed. Note the numerous eosinophils throughout the lamina propria. Distended capillaries with plump endothelial cells are present.

Case 5 - Figure 4
Higher magnification of glandular cystic dilatation with epithelial flattening, reactive atypia and apoptosis.
Case 5 - Figure 5
Clustered yttrium-90 microspheres were noted extruded into the lamina propria suggesting the diagnosis of yttrium-90 microsphere-induced gastritis after SIRT.

Discussion
The endoscopic picture shows diffuse erythematous and friable gastric mucosa. The biopsies are characterized by the presence of mucosal ulceration with diffuse reactive stromal changes with a moderate chronic inflammation. Prominent eosinophilia is observed along with capillary ectasia and prominent plump endothelial cells.

Epithelial apoptosis and mucin depletion are present in addition to cystic glandular dilatation and epithelial flattening. Foreign particles measuring about 40 microns in diameter were observed, reminiscent of psammoma bodies, but without concentric lamellation and characteristic of purple yttrium-90 SIR microspheres. Overall, the spectrum of changes is consistent with radiotherapy-induced changes.

Diagnosis:
SIR-microsphere-induced gastroduodenal ulcerations and gastritis after SIRT. (see discussion below)

Key words:
gastritis, radiation therapy, oncology, iatrogenic

Gastrointestinal Effects of Oncologic Therapy
A steady increase in the therapeutic armamentarium has been available to the oncologists. Strategies currently available, and sometimes used in a multimodal fashion, include radiotherapy, chemotherapy, immunotherapy, and targeted biologic therapies. Novel methods of delivery have also been using interventional radiology to target precisely the neoplasms (hepatic arterial infusion chemotherapy, portal vein embolization, radiofrequency ablation, cryotherapies, selective intra-artery radiation therapy)

However, no matter the care used in the tailoring and delivery of the treatment, many cancer patients develop gastrointestinal (GI) complications and particularly diarrhea, which at times can be life threatening. The prevalence and severity of these complications depends on the modalities employed. The mechanisms underlying the complications are numerous, including cellular toxicity on the proliferative zone and apoptosis, failure of normal cellular turnover, and degenerative changes of the surface epithelium. In turn, mucosal erosion, alteration of intestinal secretory function, impaired absorptive properties of the mucosa, and inflammation will be observed.

The pathological effects on the GI mucosa are rarely specific, and may offer a challenge to the surgical pathologists frequently blinded as to the exact therapeutic protocol. This short review will focus on unwanted effects of therapy on the gastrointestinal mucosa.

Radiation Therapy:
The noxious effects of radiotherapy on the GI tract are well recognized. The symptoms may vary from nausea and vomiting to diarrhea, sometimes hemorrhagic. Frequent mucosal damage includes severe ulceration of the esophagus, stomach, and large bowel. [1] Over time alteration of gut motility and of the mural integrity may be observed.

The histology of the post radiation therapy changes ranges from apoptosis, epithelial flattening, and glandular cystic dilatation to nuclear atypia, capillary ectasia as well as prominent endothelial cells. In that setting regenerative stromal, endothelial and epithelial cells may exhibit marked cellular atypia including or bizarre nuclear abnormalities, especially in the acute/subacute phase. These changes should not be misinterpreted as residual primary tumor.

Selective internal radiation therapy (SIRT) is a microbrachytherapy strategy using biocompatible resin-based yttrium-90 (90Y)-labeled microspheres administered via hepatic artery branches. SIRT has been increasingly used for the therapy to inoperable colorectal liver metastases. [2, 3] SIRT is also investigated for the treatment of HCC and metastatic neuroendocrine tumors. [3]

90Y, impregnated in 30-40 micron diameter microspheres, is a pure β-emitter with average and maximum penetration of 2.5 mm and 11 mm, respectively. [4] The physical half-life of 90Y is about two and a half days, and continual radiation emission lasts for approximately 14 days, destroying the tumor once the microspheres are trapped in the vascular bed. [5]

Since the overwhelming majority of the hepatic tumor blood supply is derived from the hepatic artery while the normal parenchyma is largely supplied by the portal vein, The SIR microspheres are administered to the targeted tumors via the hepatic artery branches.

Early reports indicate the potential benefits of this approach in selected patients. [6] However, the risk of radiation-induced toxicity may hamper the usage of this novel modality. On occasion, misdirected microspheres are caught in the capillary bed of the duodenal and/or stomach wall, and may lead to gastric and/or duodenal ulceration, bleeding, and even perforation. [2, 3, 6, 7, 8] Before initiating treatment, the risk of radiation pneumonitis should be evaluated by measuring the percentage of microspheres that pass through the hepatic circulation and eventually lodge in the pulmonary parenchyma. [5] Although embolization of the gastroduodenal artery and/or gastric arteries are common practice to avoid the migration of spheres, the retrograde migration of microspheres into the gastric or duodenal circulation, can be observed as in the case presented here. Esophagitis, pancreatitis, hepatitis with reported mortality, and cholecystitis have also been observed. [2, 6, 9] These adverse effects have been reported with an incidence ranging 0 to 13%, generally within the first 2 months after the procedure. [2, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14] A recent series of 21 patients reported a much higher rate of gastrointestinal toxicity, with gastric ulceration in 29% of the patients. Importantly, the erratic migration of the microspheres is not immediately recognized, despite sensitive radionuclide imaging to look for extrahepatic deployment. Given the recent approval by FDA for the use of SIRT, it is anticipated that more patients will be treated with this modality and that ultimately, side effects may be encountered more often.

The use of short-course neoadjuvant preoperative radiotherapy has recently been introduced for the treatment of rectal carcinoma. This short irradiation protocol followed by rapid resection has lead to the recognition of acute radiation colitis that can resolve spontaneously within a few weeks, and involved in lessened mucosal changes. In the acute phase, the histologic changes include diffuse chronic mucosal inflammation associated with prominent eosinophilia and marked epithelial damage with mucin depletion, nuclear pyknosis, karyorrhexis, and increased apoptosis. Marked regenerative atypia and cell fusion are also seen. [15] Over time, chronic architectural changes may be seen, with crypt loss or withering crypts with regenerative change. In the absence of appropriate clinical information, the changes may be mistaken for CMV colitis, ulcerative colitis, drug-induced colitis, and, less likely, ischemia and GVHD.

Over time, mucosal healing various degrees of architectural restitution and mild nonspecific chronic inflammation can be seen. Mucosal or transmural fibrosis and abnormality of vessel walls can also be observed.

It is noticeable GI complications of radiotherapy may not present for months or even years. Examples of esophageal strictures and small bowel obstructions have been reported years after the initiation of treatment and associated with chronic ischemic alterations and chronic vasculopathy of medium-sized arteries and veins with intimal fibrosis. [16] Radiation induced proctitis may also manifest itself clinically, years after radiotherapy.

Finally, in the setting of multimodality, the combination of chemotherapeutic agents (e.g. Adriamycin) has been shown to exacerbate radiotherapy induced vascular fibrinoid necrosis. [17]

Biologic Therapy
A myriad of novel biologic therapeutic agents utilizing the specificity of monoclonal antibodies (mAbs) has been developed for the treatment of various malignancies. [18, 19, 20, 21, 22, 23] Among these mAbs directed against the cytotoxic T lymphocyte antigen-4 (CTLA-4) transmembrane protein [24, 25] have been used as adjuvant therapy in the treatment of poorly immunogenic cancers such as malignant melanoma, renal cell carcinoma, and ovarian cancer. [26, 27, 28] The pathogenesis of immune dysregulation and enterocolitis following the infusion of a-CTLA-4 mAb remains unclear, but some reports have demonstrated that the administration of a-CTLA-4 mAb is associated with a decrease in Treg . [29]

The largest series reported to date observed that 21% of 198 patients receiving a-CLTA-4 mAb developed enterocolitis, usually 0 to 59 days after the last dose. [30] Diarrhea is the most common complaint, followed by abdominal pain, nausea, vomiting, and fever. The colonoscopies reported erythema and ulceration in 64% of patients while microscopic evidence of enterocolitis was present in 90% of the biopsies obtained. [30] Upper endoscopy when performed showed mucosal alterations in 63% of the patients and rare patients had histologic alterations limited to the stomach and duodenum. [30]

Microscopically, in addition to an inflammatory expansion of the lamina propria, an increased number of intraepithelial lymphocytes (IELs) and apoptosis accompanied by focal glandular inflammation can be seen along the GI tract. Architectural irregularity and blunting as well as mucin depletion can be present in the small bowel. The lamina propria may also show numerous eosinophils and scattered neutrophils. Patchy neutrophilic infiltrate of the surface epithelium and crypts (i.e., cryptitis) were present, as well as scattered epithelial apoptosis. Granulomas were absent. The changes were seen in all patients, there was variation from one to another and along the segments of GI tract. Immunohistochemistry reveals a significant increase in CD3+ lymphocytes in both LP and the intraepithelial compartment. A similar increase in LP and IEL CD4+ and CD8+ lymphocytes is also appreciated. FoxP3 immunohistochemistry shows a significant increase of this T cell subset in the LP

Overall, the constellation of pathologic findings seen after a-CLTA-4 mAb infusion may show similarities to that of graft versus host disease and autoimmune enteropathy. Infectious enteritis and early inflammatory bowel disease could also be considered in the differential diagnosis based on the morphology; however, practically, appropriate clinical information and ancillary studies are helpful in excluding the latter possibilities.

Chemotherapy
Cytotoxic chemotherapy induced changes can be seen throughout the GI tract, but are likely more marked in the small bowel, because of the increased epithelial turnover. These changes usually occur within two weeks of treatment and may persist for several weeks after completion.

The lists of chemotherapeutic agents associated with GI tract epithelial changes is long and includes antimetabolite agents such as 5-fluoro-2-deoxyuridine (FUDR), alkylating agents (cyclophosphamide), and cytotoxic antibiotics (doxorubicin).

The secondary histologic changes may include superficial erosion or ulceration associated with epithelial degenerative changes. These alterations are frequently intermixed with compensatory regenerative hyperplasia with marked mitotic activity. The overall appearance is a pattern of hyperplastic crypts and withering crypts or glands with various degree of chronic inflammation. Eosinophils are frequently numerous. Mucosal edema and prominent apoptosis are common. These changes at times may be difficult to distinguish from dysplasia or residual carcinoma.

As previously noted, the small bowel is common target of and may display villous shortening. [31] Hepatic arterial infusion chemotherapy has also been associated with severe toxicity, predominantly affecting of the duodenum and distal stomach. [32, 33, 34, 35] Rarely the changes are suggestive of a specific drug, although paclitaxel (Taxol) would be the exception with ring mitoses secondary to mitotic arrest. [36]

Gastrointestinal neuromuscular alteration leading to intestinal pseudo-obstruction has also been associated with chemotherapy. The drugs commonly associated with this presentation include vinca alkaloids and daunorubicin. [37, 38]

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