兽研两只猫因急性进行性呕吐就诊。其中一只猫（病例1）因疑似慢性炎症性肠病接受泼尼松龙治疗14个月。该猫表现为低白蛋白血症、低钴胺素血症、小肠壁增厚，超声检查显示局灶性空肠狭窄伴近端严重扩张。剖腹探查证实了狭窄，组织病理学显示黏膜下纤维增生伴轻度淋巴细胞浆细胞性肠炎。该猫于术后第12天死亡。另一只猫（病例2）超声检查显示近端小肠梗阻。对梗阻病变行宽边缘切除术。组织病理学显示轻度肠壁纤维化伴肠系膜炎症。Masson三色染色显示黏膜下胶原束。免疫组化及PCR抗原受体重排克隆性分析支持低级别肠道T细胞淋巴瘤的诊断。该猫术后恢复顺利，在泼尼松龙治疗12个月期间无再狭窄。肠道狭窄是在慢性肠病长期内科管理过程中发现的。这提示病变范围和手术切除策略可能是影响管理和预后的相关因素。
[内容请查看原文]
引言
猫慢性肠病（CE）涵盖小肠的多种疾病，包括淋巴细胞浆细胞性肠炎（LPE）和低级别肠道T细胞淋巴瘤（LGITL），这些是临床和组织学上难以区分的常见疾病（1–4）。尽管LPE和LGITL传统上分别被视为炎症性疾病和肿瘤性疾病，但它们在组织学特征、免疫表型和分子学发现上可能存在重叠。因此，即使采用WSAVA组织病理学标准、免疫组化和克隆性检测，鉴别诊断仍然具有挑战性（1–3，5–7）。这些观察支持炎症性CE与LGITL之间可能存在具有重叠特征的生物学谱系（1–4）。
在人类中，肠道纤维化是慢性炎症性肠病尤其是克罗恩病的公认特征；然而，纤维化重塑并不一定进展为具有临床意义的狭窄形成（8，9）。在猫中，引起具有临床意义的管腔狭窄或梗阻的纤维化小肠狭窄报道较少（10）。近期研究已确定肠道纤维化是猫慢性炎症性肠病中常见的组织病理学发现，且纤维化可能与不良临床结局相关（11，12）。然而，进展为具有临床意义的纤维化小肠狭窄的报道仍然很少，且在内科管理期间对该过程的纵向观察有限（10–12）。
持续性肠道炎症可能促进纤维化壁重塑，但猫中的机制仍不清楚。STAT3相关信号通路参与人类炎症性肠病的慢性肠道炎症（13）。在猫LPE和LGITL中，评估STAT3免疫反应性可能为其在肠壁重塑中的潜在参与提供探索性信息。
本报告描述了两只处于CE谱系内的猫，一只为LPE，一只为LGITL，均在长期内科管理期间发生了纤维化小肠狭窄。我们进一步描述了组织化学、免疫组化、分子学及JAK-STAT相关发现，以探讨这些病例中慢性肠道炎症、纤维化重塑与狭窄形成之间可能的关系。
[内容请查看原文]
病例描述
[内容请查看原文]
病例1
一只11岁已绝育雌性挪威森林猫因慢性呕吐转诊。体格检查显示体重3.69 kg，体况评分4/9，估计脱水7%。血清生化分析显示低白蛋白血症[1.7 g/dL；参考区间（RI），2.1–3.3 g/dL]、高球蛋白血症（5.9 g/dL；RI，2.6–5.1 g/dL）及血清钴胺素浓度降低（198 pg/mL；RI，276–1,425 pg/mL）；开始口服钴胺素。腹部超声显示弥漫性小肠壁增厚，以回盲结肠交界处最为显著（图1A，B）。怀疑CE。初始治疗包括饮食调整和支持性内科管理。由于临床反应不完全，开始泼尼松龙（1 mg/kg口服，每12小时一次）治疗并监测临床反应。
[图：病例1纤维狭窄性病变的超声和影像学表现。（A，B）腹部超声图像获自]
在随后数月中，血清白蛋白升高，回肠壁厚度减小，呕吐缓解。泼尼松龙逐渐减量，该猫保持临床稳定，约14个月内超声无明显进展。
治疗421天后，该猫出现反复呕吐、体重下降和低白蛋白血症（1.8 g/dL；参考区间2.1–3.3 g/dL）。重复腹部超声检查发现新的空肠中段狭窄性病变，伴近端小肠扩张（图1C）。两天后出现急性厌食，X线摄影和超声检查证实机械性小肠梗阻（图1D,E）。行剖腹探查术、肠段切除及端端空肠-空肠吻合术。组织病理学显示淋巴细胞-浆细胞性肠炎伴节段性纤维狭窄性病变、黏膜下纤维增生、成熟肉芽组织及显著黏膜下纤维化（图2A）。Masson三色染色显示黏膜下胶原沉积（图2C）。免疫组化显示以CD3阳性T淋巴细胞为主，PAX5阳性B细胞极少（图2E,G）。另进行JAK-STAT相关免疫组化检测总STAT3、总STAT5b和磷酸化JAK1。一抗及对照品的详细信息见补充表1。对每个评估细胞群体在约五个代表性显微镜视野中进行半定量免疫标记评估。肉眼估计免疫反应细胞比例，染色强度分为弱、中、强。总STAT3染色在固有层淋巴细胞中呈强多灶性，在肠上皮细胞中呈弥漫中度，在黏膜下淋巴细胞和成纤维细胞中呈弥漫强阳性（图3A,C）。总STAT5b在固有层淋巴细胞中呈强多灶性表达，在肠上皮细胞中呈弥漫弱染色，在黏膜下淋巴细胞中呈散在阳性（图3E）。磷酸化JAK1在固有层淋巴细胞中呈强多灶性染色，在肠上皮细胞中主要呈弱胞质免疫反应性，小部分细胞呈散在强染色（图3G）。半定量免疫组化结果总结于补充表2。
[图：本病例中纤维狭窄性病变的组织病理学和免疫表型结果。（A,B）H&E染色的s]
[图：病例1和2中JAK-STAT相关免疫组化结果。（A,B）肠黏膜中总STAT3免疫反应性]
术后恢复初期顺利，出院后食欲和粪便质量恢复正常。然而，该猫在术后第12天在家中突然死亡。
[内容请查看原文]
病例2
一只13岁去势雄性家养短毛猫因2个月慢性呕吐和进行性体重下降转诊评估。就诊时，临床病理学异常包括贫血，表现为红细胞压积降低（19.8%；参考区间30.3–52.3%）、低白蛋白血症（1.3 g/dL；参考区间2.1–3.3 g/dL）以及血清淀粉样蛋白A浓度显著升高（430 μg/mL；参考区间0–10 μg/mL）。腹部X线摄影显示严重节段性小肠扩张（图4A）。超声检查显示降十二指肠突然狭窄伴近端扩张、弥漫性肌层增厚及轻度肠系膜淋巴结肿大（图4B,C）。对比增强计算机断层扫描（CT）显示局灶性空肠狭窄性病变导致机械性梗阻（图4D,E）。剖腹探查术发现一段明显炎症的空肠段包含狭窄区域，行包括相邻肉眼正常肠管的宽边缘切除，随后行端端吻合术。切除空肠段的组织病理学检查显示纤维炎性肠炎伴纤维化及继发性狭窄形成（图2B）。Masson三色染色显示胶原沉积（图2D）。免疫组化显示以CD3阳性T细胞浸润为主，未检测到PAX5阳性B细胞浸润（图2F,H）。使用从福尔马林固定、石蜡包埋空肠组织中提取的DNA进行抗原受体基因重排聚合酶链反应（PARR）（VDx Veterinary Diagnostics, Davis, CA, USA）。使用已发表的针对猫T细胞受体γ（TRG）及免疫球蛋白重链框架2和3区的修订引物，扩增产物通过毛细管电泳分析（14,15）。鉴定出克隆性TRG模式，结合组织病理学和免疫表型结果，支持LGITL的诊断。
[图：病例2中导致机械性小肠梗阻的纤维狭窄性病变的医学影像学结果。（A）腹]
额外免疫组化染色显示中等比例黏膜淋巴细胞呈弥漫性胞质STAT3免疫反应性，肠上皮细胞呈弥漫强胞质免疫反应性。在黏膜下，巨噬细胞、中性粒细胞和成纤维细胞中观察到弥漫性STAT3免疫反应性（图3B,D）。STAT5b免疫组化显示黏膜淋巴细胞中罕见胞质免疫反应性，肠上皮细胞中呈弥漫弱胞质免疫反应性，黏膜下巨噬细胞和中性粒细胞中呈散在弱胞质免疫反应性（图3F）。磷酸化JAK1免疫组化显示黏膜肠上皮细胞主要呈弱胞质免疫反应性，小部分细胞呈散在强染色（图3H）。半定量免疫组化结果总结于补充表2。
由于担心化疗相关不良反应，主人选择了泼尼松龙单药治疗。猫在肠切除术后约1年内保持相对稳定。随访期间，在泼尼松龙减量过程中临床症状和超声肠道壁增厚加重，剂量增加后改善。随后手术部位出现疑似复发性狭窄性病变伴部分梗阻，但管腔通畅性得以维持。
在进一步临床进展后，加用了苯丁酸氮芥（2 mg/猫，口服，隔日一次）。临床症状重新稳定，泼尼松龙逐渐减量。然而，体重减轻、厌食和弥漫性小肠壁增厚复发。末次随访检查时未观察到狭窄段明显进展。尽管给予支持性护理，猫在肠切除术后502天死亡。
[内容请查看原文]
讨论
与既往描述肠道狭窄或组织病理学纤维化的报道不同，本两例展示了猫慢性肠病（CE）病程中与纤维狭窄性重塑相关的纵向临床和影像学变化（10–12）。病例1中，弥漫性壁异常先于局灶性空肠狭窄；病例2表现为复发性壁增厚和术后再狭窄。两只猫均在炎症性和肿瘤性CE中发生了纤维狭窄性疾病。
两例均显示胶原沉积、纤维化壁重塑和管腔狭窄，但纤维化的背景不同。病例1中，纤维化与非肿瘤性淋巴浆细胞性炎症、黏膜下纤维增生和成熟肉芽组织相关。病例2中，纤维化与克隆性肿瘤性T细胞浸润及炎症和间质反应相关。因此，LPE和LGITL在淋巴增殖过程和纤维化背景上不同，但共享一种形态学上与克罗恩病所述相似的纤维狭窄表型，但不意味着致病等同（8, 9）。因此，类似的炎症相关纤维化过程可能促成了这些病例中狭窄的形成（10–12）。
STAT3相关信号可能连接持续性肠道炎症、淋巴瘤相关细胞相互作用和纤维狭窄性重塑（13, 16）。在人类纤维狭窄性克罗恩病中，肠道间充质细胞中的STAT3信号增加TGF-β1转录和I型胶原产生（16）。在这些病例中，纤维狭窄性病变的淋巴样和间质细胞中检测到STAT3免疫反应性。病例1中，其在固有层和黏膜下淋巴细胞及成纤维细胞中呈强阳性。病例2中，在黏膜淋巴细胞、黏膜下巨噬细胞、中性粒细胞和成纤维细胞中检测到。半定量评估进一步显示，两例中所评估细胞群体间STAT3免疫反应性的范围和强度存在差异（补充表2）。这些发现提示STAT3相关信号与这些病例纤维狭窄性病变中炎症-间质相互作用之间可能存在关联。
尽管观察到的免疫反应性不能确立STAT3在纤维化中的因果作用，但两个纤维狭窄性病变中STAT3免疫反应性的检测为进一步研究JAK-STAT3通路作为猫纤维狭窄性CE的潜在治疗靶点提供了依据。在人类中，选择性JAK1抑制剂upadacitinib对中重度克罗恩病有效（17）。直接抑制STAT3可改善实验性结肠炎并减少狭窄性克罗恩病肠道来源细胞中的促纤维化信号（16, 18），支持研究通过调节以减少猫持续性肠道炎症及随后的纤维狭窄性重塑。
鉴于JAK-STAT信号参与肠道炎症且两个纤维狭窄性病变中总STAT3免疫反应性均存在，oclacitinib——一种用于猫的兽医JAK1偏好性抑制剂——可能是猫CE药物重定位研究的临床可及候选药物（19）。然而，目前不推荐将其用于该病症。
两只猫术后病程不同也可能反映手术范围和残留显微镜下病变的差异。病例1中，切除限于肉眼狭窄段，黏膜下纤维增生伴中度淋巴浆细胞浸润延伸至送检组织远端边缘，提示显微镜下病变超出可见病变。病例2中，宽边缘切除包括相邻肉眼正常肠段，可能减少了残留显微镜下病变并有助于延长术后稳定期。这些发现提示手术切除范围可能与疑似纤维狭窄性肠病猫的术后结局相关。
本研究的局限性包括：病例1为推测性临床诊断，仅纳入两只基础诊断、组织学纤维化分布、治疗及手术方式均不同的猫，病例1猝死原因不明，未进行尸检，且总STAT3免疫组化无法确定STAT3相关信号是否参与纤维狭窄性重塑，也无法确定观察到的免疫反应性是否反映猫慢性肠病中慢性炎症和组织重塑的继发性反应。仍需进一步研究猫慢性肠病肠道纤维化中STAT3相关信号通路。
[内容请查看原文]
结论
这些病例为猫慢性肠病纤维狭窄的谱系增添了新的临床观察。这两只猫所观察到的相似纤维狭窄表型提示，猫慢性肠病的炎症性和肿瘤性形式可能发生可比的结构性重塑。连续影像学记录了疾病进展和疑似术后复发，而两处病变中总STAT3免疫反应性均支持研究与猫慢性肠病相关肠道纤维化中的JAK-STAT3信号传导。其他局限性包括缺乏专用阴性对照切片以及对免疫标记进行客观定量图像分析。仍需进一步研究以确定调节JAK-STAT3通路能否改变纤维狭窄进展或术后复发。
查看英文原文▾
Two cats presented with acute progressive vomiting. One cat (Case 1) received prednisolone for suspected chronic inflammatory enteropathy for 14 months. The cat showed hypoalbuminemia, hypocobalaminemia, small intestinal thickening, and focal jejunal stricture with severe proximal dilation on ultrasonography. Exploratory laparotomy confirmed the stricture, and histopathology revealed submucosal fibroplasia with mild lymphoplasmacytic enteritis. The cat died on postoperative day 12. Another cat (Case 2) showed proximal small intestinal obstruction on ultrasonography. A wide-margin resection of the obstructed lesion was performed. Histopathology revealed mild intestinal wall fibrosis with mesenteric inflammation. Masson’s trichrome staining showed submucosal collagen bundles. Immunohistochemistry and clonality analysis by PCR for antigen receptor rearrangement supported the diagnosis of low-grade intestinal T-cell lymphoma. The cat recovered uneventfully and remained restenosis-free during prednisolone treatment for 12 months after surgery. Intestinal stenoses were identified during long-term medical management of chronic enteropathy. This suggests that the extent of the lesion and the surgical resection strategy could be relevant factors for management and prognosis.
[内容请查看原文]
Introduction
Chronic enteropathy (CE) in cats encompasses various disorders of the small intestine, including lymphoplasmacytic enteritis (LPE) and low-grade intestinal T-cell lymphoma (LGITL), which are common entities that are difficult to distinguish clinically and histologically (1–4). Although LPE and LGITL have traditionally been regarded as inflammatory and neoplastic disorders, respectively, they can overlap in histologic features, immunophenotypes, and molecular findings. Thus, differentiation remains challenging even with WSAVA histopathological criteria, immunohistochemistry, and clonality testing (1–3, 5–7). These observations support the existence of a possible biological spectrum with overlapping features between inflammatory CE and LGITL (1–4).
In humans, intestinal fibrosis is a recognized feature of chronic inflammatory bowel disease, particularly Crohn’s disease; however, fibrotic remodeling does not necessarily progress to clinically relevant stricture formation (8, 9). In cats, fibrotic small intestinal strictures causing clinically relevant luminal narrowing or obstruction have been reported less frequently (10). Recent studies have identified intestinal fibrosis as a frequent histopathological finding in cats with chronic inflammatory enteropathy, and fibrosis may be associated with unfavorable clinical outcomes (11, 12). However, progression to clinically relevant fibrotic small intestinal strictures remains poorly documented, and longitudinal observation of this process during medical management is limited (10–12).
Persistent intestinal inflammation may contribute to fibrotic mural remodeling, but mechanisms in cats remain unclear. STAT3-related signaling is implicated in chronic intestinal inflammation in human inflammatory bowel disease (13). In feline LPE and LGITL, evaluation of STAT3 immunoreactivity may provide exploratory information regarding its potential involvement in intestinal wall remodeling.
This report describes two cats within the CE spectrum, one with LPE and one with LGITL, each of which developed a fibrotic small intestinal stricture during long-term medical management. We further describe histochemical, immunohistochemical, molecular, and JAK-STAT-related findings to explore the possible relationship among chronic intestinal inflammation, fibrotic remodeling, and stricture formation in these cases.
[内容请查看原文]
Case description
[内容请查看原文]
Case 1
An 11-year-old spayed female Norwegian Forest cat was referred for chronic vomiting. Physical examination revealed body weight of 3.69 kg, body condition score of 4/9, and estimated 7% dehydration. Serum biochemical analysis revealed hypoalbuminemia [1.7 g/dL; reference interval (RI), 2.1–3.3 g/dL], hyperglobulinemia (5.9 g/dL; RI, 2.6–5.1 g/dL), and decreased serum cobalamin concentration (198 pg/mL; RI, 276–1,425 pg/mL); oral cobalamin was initiated. Abdominal ultrasonography revealed diffuse small intestinal wall thickening, most prominently at the ileocecocolic junction (Figures 1A,B). CE was suspected. Initial treatment included dietary modification and supportive medical management. As the clinical response was incomplete, prednisolone (1 mg/kg PO every 12 h) was initiated and the clinical response to treatment was monitored.
[图：Ultrasound and radiographic findings of the fibrostenotic lesion in Case 1. (A,B) Abdominal ultrasonographic images obta]
Over the following months, serum albumin increased, ileal wall thickness decreased, and vomiting resolved. Prednisolone was tapered, and the cat remained clinically stable without substantial ultrasonographic progression for approximately 14 months.
After 421 days of treatment, the cat developed recurrent vomiting, weight loss, and hypoalbuminemia (1.8 g/dL; RI, 2.1–3.3 g/dL). A repeat abdominal ultrasonography revealed a new midjejunal stenotic lesion with proximal small intestinal dilation (Figure 1C). Two days later, acute anorexia developed, and radiography and ultrasonography confirmed mechanical small intestinal obstruction (Figures 1D,E). Exploratory laparotomy, segmental resection, and end-to-end jejunojejunal anastomosis were performed. Histopathology revealed LPE with a segmental fibrostenotic lesion, submucosal fibroplasia, mature granulation tissue, and marked submucosal fibrosis (Figure 2A). Masson’s trichrome staining revealed submucosal collagen deposition (Figure 2C). Immunohistochemistry showed predominantly CD3-positive T lymphocytes and few PAX5-positive B cells (Figures 2E,G). Additional JAK-STAT-related immunohistochemistry was performed for total STAT3, total STAT5b, and phospho-JAK1. Details of the primary antibodies and controls are provided in Supplementary Table 1. Immunolabeling was evaluated semi-quantitatively in approximately five representative microscopic fields for each evaluated cell population. The proportion of immunoreactive cells was visually estimated, and staining intensity was categorized as weak, moderate, or strong. Total STAT3 staining was strongly multifocal in lamina propria lymphocytes, diffusely moderate in enterocytes, and diffusely strong in submucosal lymphocytes and fibroblasts (Figures 3A,C). Total STAT5b showed strong multifocal expression in lamina propria lymphocytes, diffuse weak staining in enterocytes, and scattered positivity in submucosal lymphocytes (Figure 3E). Phospho-JAK1 displayed strong multifocal staining in lamina propria lymphocytes and predominantly weak cytoplasmic immunoreactivity in enterocytes, with scattered strong staining in a small proportion of cells (Figure 3G). The semi-quantitative immunohistochemical findings are summarized in Supplementary Table 2.
[图：Histopathologic and immunophenotypic findings of the fibrostenotic lesions in the present cases. (A,B) H&E-stained s]
[图：JAK-STAT-related immunohistochemical findings in Cases 1 and 2. (A,B) Total STAT3 immunoreactivity in the intestinal muc]
Postoperative recovery was initially uneventful, and appetite and fecal quality normalized after discharge. However, the cat died suddenly at home on postoperative day 12.
[内容请查看原文]
Case 2
A 13-year-old neutered male domestic shorthair cat was referred for the evaluation of a 2-month history of chronic vomiting and progressive weight loss. On presentation, clinicopathologic abnormalities included anemia, indicated by a decreased packed cell volume (19.8%; RI, 30.3–52.3%), hypoalbuminemia (1.3 g/dL; RI, 2.1–3.3 g/dL), and a marked increase in serum amyloid A concentration (430 μg/mL; RI, 0–10 μg/mL). Abdominal radiography revealed severe segmental small-intestinal dilation (Figure 4A). Ultrasonography revealed an abrupt stenosis of the descending duodenum with proximal dilation, diffuse muscularis thickening, and mild mesenteric lymphadenopathy (Figures 4B,C). Contrast-enhanced computed tomography (CT) revealed a focal jejunal stenotic lesion causing mechanical obstruction (Figures 4D,E). Exploratory laparotomy identified a markedly inflamed jejunal segment containing the stenotic region, and wide-margin resection including the adjacent grossly normal bowel was performed, followed by end-to-end anastomosis. Histopathological examination of the resected jejunal segment revealed fibro-inflammatory enteritis with fibrosis and secondary stricture formation (Figure 2B). Masson’s trichrome staining revealed collagen deposition (Figure 2D). Immunohistochemistry demonstrated predominantly CD3-positive T-cell infiltration with no detectable PAX5-positive B-cell infiltrates (Figures 2F,H). Polymerase chain reaction for antigen receptor rearrangement (PARR) was performed (VDx Veterinary Diagnostics, Davis, CA, USA) using DNA extracted from formalin-fixed, paraffin-embedded jejunal tissue. Published revised primers targeting feline T-cell receptor gamma (TRG) and immunoglobulin heavy-chain framework 2 and 3 regions were used, and the amplicons were analyzed by capillary electrophoresis (14, 15). A clonal TRG pattern was identified, which, together with the histopathologic and immunophenotypic findings, supported the diagnosis of LGITL.
[图：Medical imaging findings of the fibrostenotic lesion causing mechanical small intestinal obstruction in Case 2. (A) Vent]
Additional immunohistochemical staining revealed diffuse cytoplasmic STAT3 immunoreactivity in a moderate proportion of mucosal lymphocytes and diffuse strong cytoplasmic immunoreactivity in enterocytes. In the submucosa, diffuse STAT3 immunoreactivity was observed in macrophages, neutrophils, and fibroblasts (Figures 3B,D). STAT5b immunohistochemistry revealed rare cytoplasmic immunoreactivity in mucosal lymphocytes, diffuse weak cytoplasmic immunoreactivity in enterocytes, and scattered weak cytoplasmic immunoreactivity in submucosal macrophages and neutrophils (Figure 3F). Phospho-JAK1 immunohistochemistry showed predominantly weak cytoplasmic immunoreactivity in mucosal enterocytes, with scattered strong staining in a small proportion of cells (Figure 3H). The semi-quantitative immunohistochemical findings are summarized in Supplementary Table 2.
The owner elected prednisolone monotherapy due to chemotherapy-related adverse effect concerns. The cat remained relatively stable for approximately 1 year after intestinal resection. During follow-up, clinical signs and ultrasonographic intestinal wall thickening worsened during prednisolone tapering and improved after dose escalation. A suspected recurrent stenotic lesion with partial obstruction subsequently developed at the surgical site, although luminal patency was maintained.
After further clinical progression, chlorambucil (2 mg/cat PO every other day) was added. Clinical signs re-stabilized, and prednisolone was gradually tapered. However, weight loss, anorexia, and diffuse small-intestinal wall thickening recurred. Marked progression of the narrowed segment was not observed during the final follow-up examination. Despite supportive care, the cat died 502 days after the intestinal resection.
[内容请查看原文]
Discussion
Unlike previous reports describing intestinal strictures or histopathologic fibrosis, the present two cases illustrate longitudinal clinical and imaging changes associated with fibrostenotic remodeling during the course of feline CE (10–12). In Case 1, diffuse mural abnormalities preceded a focal jejunal stricture; Case 2 showed recurrent mural thickening and postoperative restenosis. Both cats developed fibrostenotic disease in inflammatory and neoplastic CE.
Both cases showed collagen deposition, fibrotic mural remodeling, and luminal narrowing, but the context of fibrosis differed. In Case 1, fibrosis was associated with non-neoplastic lymphoplasmacytic inflammation, submucosal fibroplasia, and mature granulation tissue. In Case 2, it was associated with clonal neoplastic T-cell infiltration and inflammatory and stromal responses. Thus, LPE and LGITL differ in the lymphoid process and fibrosis context but share a fibrostenotic phenotype that is morphologically similar to that described in Crohn’s disease, without implying pathogenic equivalence (8, 9). Therefore, a comparable inflammation-associated fibrotic process may have contributed to stricture formation in these cases (10–12).
STAT3-related signaling may link persistent intestinal inflammation, lymphoma-associated cellular interactions, and fibrostenotic remodeling (13, 16). In humans with fibrostenotic Crohn’s disease, STAT3 signaling in intestinal mesenchymal cells increases TGF-β1 transcription and type I collagen production (16). In these cases, STAT3 immunoreactivity was identified in lymphoid and stromal cells in fibrostenotic lesions. In Case 1, it was strong in lamina propria and submucosal lymphocytes and fibroblasts. In Case 2, it was identified in mucosal lymphocytes, submucosal macrophages, neutrophils, and fibroblasts. Semi-quantitative evaluation further demonstrated variation in the extent and intensity of STAT3 immunoreactivity among the evaluated cell populations in both cases (Supplementary Table 2). These findings suggest a possible association between STAT3-related signaling and inflammatory-stromal interactions in the fibrostenotic lesions of these cases.
Although the observed immunoreactivity does not establish a causal role for STAT3 in fibrosis, the detection of STAT3 immunoreactivity in both fibrostenotic lesions provides a rationale for further investigation of the JAK-STAT3 pathway as a potential therapeutic target in feline fibrostenotic CE. In humans, the selective JAK1 inhibitor upadacitinib is effective for moderate-to-severe Crohn’s disease (17). Direct STAT3 inhibition ameliorated experimental colitis and reduced profibrotic signaling in strictured Crohn’s disease intestine-derived cells (16, 18), supporting investigation of modulation to reduce persistent intestinal inflammation and subsequent fibrostenotic remodeling in cats.
Given JAK-STAT signaling involvement in intestinal inflammation and total STAT3 immunoreactivity in both fibrostenotic lesions, oclacitinib, a veterinary JAK1-preferential inhibitor administered to cats, may be a clinically accessible candidate for drug-repurposing studies on feline CE (19). However, its use is not currently recommended for this condition.
The different postoperative courses in the two cats may also reflect differences in the surgical extent and residual microscopic disease. In Case 1, resection was limited to the grossly stenotic segment, and submucosal fibroplasia with moderate lymphoplasmacytic infiltration extended to the distal edge of the submitted tissue, suggesting microscopic extension beyond the visible lesion. In Case 2, wide-margin resection included an adjacent grossly normal bowel, which may have reduced residual microscopic disease and contributed to prolonged postoperative stability. These findings suggest that the extent of surgical resection might be relevant to postoperative outcome in cats with suspected fibrostenotic enteropathy.
The limitations of this study included the presumptive clinical diagnosis in Case 1, only two cats with different underlying diagnoses, histologic fibrosis distributions, treatments, and surgical approaches, unknown cause of sudden death in Case 1, no postmortem examination, and inability of total STAT3 immunohistochemistry to determine whether STAT3-related signaling contributes to fibrostenotic remodeling or whether the observed immunoreactivity reflects a secondary response to chronic inflammation and tissue remodeling in feline CE. Further studies of STAT3-related signaling pathways in intestinal fibrosis in feline CE are required.
[内容请查看原文]
Conclusion
These cases add new clinical observations to the spectrum of fibrostenosis in cats with CE. The similar fibrostenotic phenotype observed in these two cats suggests that comparable structural remodeling might occur in both inflammatory and neoplastic forms of feline CE. Serial imaging documented progression and suspected postoperative recurrence, while total STAT3 immunoreactivity in both lesions supports investigating JAK-STAT3 signaling in feline intestinal fibrosis related to CE. Additional limitations included the lack of dedicated negative-control sections and objective quantitative image analysis of immunolabeling. Further studies are needed to determine whether modulation of the JAK-STAT3 pathway can alter fibrostenotic progression or postoperative recurrence.