消化道病理(二)

1、炎症性肠病的临床病理炎症性肠病的临床病理 THE CLINICO-PATHOLOGY OF INFLAMMATORY BOWEL DISEASE (IBD)2015-11-24溃疡性结肠炎（溃疡性结肠炎（Ulcerative colitis）克罗思病（克罗思病（Crohns disease）未定型结肠炎（未定型结肠炎（Indeterminate colitis）IBM一词主要是指两种肠病：克罗思病和溃疡性结肠炎。两者临床病一词主要是指两种肠病：克罗思病和溃疡性结肠炎。两者临床病程与病史不同，病变有别，但某些特点相同，而治疗原则不同。程与病史不同，病变有别，但某些特点相同，而治疗原则不同。 In

2、flammatory bowel disease is a term that describes two diseases: Crohn disease and ulcerative colitis. Although these two disorders have different clinical courses as well as natural histories and are usually clearly distinguishable, they have certain common features.无特异性实验室检测指标（无特异性实验室检测指标（No specif

3、ic laboratory tests）抗中性粒细胞胞质抗体抗中性粒细胞胞质抗体 pANCA (anti-neutrophil cytoplasmic antibody) 60-75%的溃疡性结肠炎病例（的溃疡性结肠炎病例（Ulcerative colitis: 60-75%） 10-40%的克罗思病病例（的克罗思病病例（Crohns disease: 10-40%）抗酿酒酵母菌抗体抗酿酒酵母菌抗体 ASCA (anti-Saccharomyces cerevisiae antibody) 40-80%的溃疡性结肠炎病例（的溃疡性结肠炎病例（Crohns disease: 40-80%） 10

4、%的克罗思病病例（的克罗思病病例（Ulcerative colitis: 10%）基因检测：基因检测： NOD2 和其他的和其他的IBD 基因基因 （Genetic testing for NOD2 and other IBD genes）IBD的实验室检测的实验室检测克罗恩病克罗恩病（Crohn Disease） 克罗恩病（克罗恩病（Crohn Disease） 肠炎特点（肠炎特点（Features of Inflammation of the Intestine） 慢性，节段性，透壁性慢性，节段性，透壁性（Chronic, Segmental, Transmural） 病变以病变以小肠远端

5、为主，右半结肠可受累小肠远端为主，右半结肠可受累，可有消化道甚至肠，可有消化道甚至肠外组织受累外组织受累 （Crohn disease occurs principally in the distal small intestine but may involve any part of the digestive tract and even extraintestinal tissues. The colon, particularly the right colon, may be affected.）2022-3-26克罗恩病的流行病学（克罗恩病的流行病学（Epidemiology）

6、全球发生克罗思病，每年发病率为全球发生克罗思病，每年发病率为0.5 - 5 人人/ 每每10万人群万人群。过去。过去30年来，来自各国的报道表明，全球的克罗思发病年来，来自各国的报道表明，全球的克罗思发病率急剧增加。率急剧增加。 （Crohn disease occurs worldwide, with an annual incidence of 0.5 to 5 per 100,000. Reports from various countries indicate that the incidence has increased dramatically over the past 30

7、 years. ） 欧洲的该病病例最常见于青少年或年轻成人欧洲的该病病例最常见于青少年或年轻成人,犹太人群呈犹太人群呈高发病率，女性较男性稍微多见高发病率，女性较男性稍微多见(1.6:1). The disease usually appears in adolescents or young adults and is most common among persons of European origin, with a considerably higher frequency in the Jewish population. There is a slight female pred

8、ominance (1.6:1).2022-3-26发病机制（发病机制（Pathogenesis） 家族性遗传性体质家族性遗传性体质 Concordance rates in twin pairs and siblings strongly implicate a genetic predisposition to Crohn disease. A family history of inflammatory bowel disease is more common for Crohn disease than for ulcerative colitis. A putative suscep

9、tibility locus for Crohn disease has been assigned to the centromeric region of chromosome 16 where it is associated with the NOD2/CARD15 locus, which codes for an intracellular receptor for bacterial products involved in innate immunity. 自身免疫机制自身免疫机制 The possibility that Crohn disease reflects immu

10、nologically mediated damage to the intestine is suggested by (1) the chronic and recurrent nature（慢性反复发作） of the inflammation and (2) its association with systemic manifestations（全身损害） that are suggestive of autoimmune disease. Most recent immunologic studies focus on the possible role of cell-media

11、ted cytotoxicity.2022-3-26 肠道粪便流的作用肠道粪便流的作用 The fecal stream appears to be of prime importance in the pathogenesis of Crohn disease, as evidenced by：(1) the beneficial effects of surgical bypass（肠旁路吻合的好处）（肠旁路吻合的好处）(2) the pattern of preanastomotic recurrence in patients with side-to-end anastomotic

12、sites（侧（侧-端吻合处前段复发）端吻合处前段复发）, and (3) the frequency of early inflammatory lesions (aphthoid erosions) in the epithelium in association with mucosal lymphoid tissue（淋巴组织增生之（淋巴组织增生之上皮处早期炎症上皮处早期炎症-口疮样糜烂）口疮样糜烂）.2022-3-26病理变化（病理变化（Pathology） 克罗思病有两大病变特征，以此与其他的炎症性肠病相鉴别：克罗思病有两大病变特征，以此与其他的炎症性肠病相鉴别： Two majo

13、r characteristics of Crohn disease differentiate it from other GI inflammatory diseases. 第一，严重通常累及肠壁全层，故称之为第一，严重通常累及肠壁全层，故称之为透壁性炎症透壁性炎症。 First, the inflammation usually involves all layers of the bowel wall and is, therefore, referred to as transmural inflammatory disease. 第二，第二，肠壁病变是间断性的肠壁病变是间断性的，即

14、节段性肠炎病变，间有未受累，即节段性肠炎病变，间有未受累及的正常肠组织及的正常肠组织 Second, the involvement of the intestine is discontinuous; that is, segments of inflamed tissue are separated by apparently normal intestine.2022-3-26克罗恩病病变分布的四大部位特征克罗恩病病变分布的四大部位特征(1)回盲部回盲部病变为主，占病变为主，占50% mainly the ileum and cecum in about 50% of cases(2)仅

15、有仅有小肠小肠病变，占病变，占15% only the small intestine in 15%(3)仅有仅有大肠大肠病变，占病变，占20% only the colon in 20%(4)肛门直肠肛门直肠区病变为主，占区病变为主，占15% 女性肛门直肠区克罗恩病可蔓延到外阴部女性肛门直肠区克罗恩病可蔓延到外阴部 mainly the anorectal region in 15%. In women with anorectal Crohn disease, the inflammation may spread to involve the external genitalia.202

16、2-3-26大体观大体观(Grossly )肠壁与邻近肠系膜增厚，水肿，肠系膜脂肪环绕肠周（肠壁与邻近肠系膜增厚，水肿，肠系膜脂肪环绕肠周（爬行脂肪爬行脂肪） The bowel and adjacent mesentery are thickened as well as edematous, and mesenteric fat often wraps around the bowel (Creeping fat). 肠系膜淋巴结肠系膜淋巴结常常肿大，变硬，相互融合常常肿大，变硬，相互融合 Mesenteric lymph nodes are frequently enlarged, fi

17、rm, and matted together. 肠腔狭窄肠腔狭窄（水肿与纤维化共同作用所致），可见鹅卵石状外观（因结（水肿与纤维化共同作用所致），可见鹅卵石状外观（因结节状肿胀、肠壁纤维化和粘膜溃疡所致）节状肿胀、肠壁纤维化和粘膜溃疡所致） The intestinal lumen is narrowed by a combination of edema and fibrosis. Nodular swelling, fibrosis, and mucosal ulceration lead to a cobblestone appearance . 溃疡特点：溃疡特点：早期早期的溃疡呈的

18、溃疡呈口疮状口疮状或葡行状；或葡行状；晚期晚期的溃疡变深呈的溃疡变深呈线状线状裂缝或裂纹状裂缝或裂纹状 In early cases, ulcers have either an aphthous or a serpiginous appearance; later, they become deeper and appear as linear clefts or fissures (see Fig. 13-23B).2022-3-26图片图片A.A.末端回肠远端肠壁明显增厚末端回肠远端肠壁明显增厚，伴有回盲瓣变形。可见一，伴有回盲瓣变形。可见一纵向溃纵向溃疡疡 ( (箭头所示箭头所示) )

19、图片图片B. B. 该回肠节段另一该回肠节段另一纵向溃疡纵向溃疡。受损粘膜水肿，形成圆形。受损粘膜水肿，形成圆形/ /卵圆卵圆形结节状隆起，使病变肠段粘膜呈形结节状隆起，使病变肠段粘膜呈鹅卵石样外观。右下侧局部粘膜部鹅卵石样外观。右下侧局部粘膜部分未受累分未受累2022-3-26 克罗恩病肠切除标本大体观克罗恩病肠切除标本大体观大体切面观大体切面观 The cut surface of the bowel wall shows the transmural （透壁性）nature of the disease, with thickening（增厚）, edema（水肿）, and fibro

20、sis（纤维化） of all layers. Involved loops of bowel are often adherent（粘连）, and fistulas（瘘管瘘管） between such segments are frequent. These fistulas may also penetrate from the bowel into other organs（肠壁瘘管穿入其它器官）, including the bladder, uterus, vagina, and skin. Lesions in the distal rectum and anus may cr

21、eate perianal fistulas（肛旁瘘）, a well-known presenting feature.2022-3-26Microscopically, Crohn disease appears as a chronic inflammatory process. During early phases of the disease, the inflammation may be confined to（局限于） the mucosa and submucosa. Small, superficial mucosal ulcerations (aphthous ulce

22、rs口疮样溃疡) are seen. Later, long, deep, fissure-like（裂隙状） ulcers are seen, and vascular hyalinization and fibrosis become apparent.The microscopic hallmark of Crohn disease is transmural, nodular, lymphoid aggregates (Fig. 13-24). Discrete（散在的）, noncaseating（非干酪样） granulomas（肉芽肿）, mostly in the submuc

23、osa, may be present. Although the presence of granulomas is strong evidence in favor of Crohn disease, less than half of the cases show these lesions. The pathologic features of Crohn disease are summarized in Figure 13-25.2022-3-26正常的结肠粘膜组织结构正常的结肠粘膜组织结构Figure 13-24. 克罗恩病克罗恩病. 图片图片A显示溃疡至粘膜下层；淋巴组织聚集在

24、粘膜下显示溃疡至粘膜下层；淋巴组织聚集在粘膜下、邻近肌层和浆膜下。图片、邻近肌层和浆膜下。图片B显示粘膜活检，可见小灶上皮样肉芽肿位于两显示粘膜活检，可见小灶上皮样肉芽肿位于两个无损的腺隐窝之间。个无损的腺隐窝之间。 A. The colon involved with Crohn disease shows an area of mucosal ulceration, an expanded submucosa with lymphoid aggregates, and numerous lymphoid aggregates in the subserosal tissues immedi

25、ately adjacent to the muscularis externa. B. This mucosal biopsy in Crohn disease shows a small epithelioid granuloma (arrows) between two intact crypts.2022-3-26克罗恩病的肉芽肿病变克罗恩病的肉芽肿病变克罗恩病肉芽肿的高倍镜下观克罗恩病肉芽肿的高倍镜下观大肠腺上皮隐窝结构变形大肠腺上皮隐窝结构变形克罗恩病回肠炎克罗恩病回肠炎下图见裂缝状溃疡下图见裂缝状溃疡逆流性回肠炎逆流性回肠炎克罗恩病肠道活检克罗恩病肠道活检H-E染色切片组织学观察

26、染色切片组织学观察箭头所示克罗恩病的透壁性炎症箭头所示克罗恩病的透壁性炎症临床特点临床特点(Clinical Features) 克罗恩病的临床表现与病史各自不同，与发病部位相关克罗恩病的临床表现与病史各自不同，与发病部位相关 The clinical manifestations and natural history of Crohn disease are highly variable and relate to the anatomical sites involved by the disease. 最常见症状：最常见症状：75%病人腹痛腹泻；病人腹痛腹泻；50%病人回归热病人回归

27、热The most frequent symptoms are abdominal pain and diarrhea, which are seen in more than 75% of patients, and recurrent fever, evident in 50%. 吸收不良和营养不良；腹泻和肠出血；以直肠肛门病变为吸收不良和营养不良；腹泻和肠出血；以直肠肛门病变为主的可反复发生肛瘘主的可反复发生肛瘘 When the small intestine is diffusely involved, malabsorption and malnutrition may be ma

28、jor features. Crohn disease of the colon leads to diarrhea and sometimes colonic bleeding. In a few patients, the major site of involvement is the anorectal region, and recurrent anorectal fistulas may be the presenting sign.2022-3-26克罗恩病的继发病变克罗恩病的继发病变肠道阻塞、瘘管和肠穿孔肠道阻塞、瘘管和肠穿孔Intestinal obstruction and

29、 fistulas are the most common intestinal complications of Crohn disease. Occasionally, free perforation of the bowel occurs. 发生肠癌发生肠癌 Small bowel cancer is at least threefold more common in patients with Crohn disease, and the disease also predisposes to colorectal cancer.No cure for Crohn disease i

30、s available. Several medications suppress the inflammatory reaction, including corticosteroids, sulfasalazine, metronidazole, 6-mercaptopurine, cyclosporine, and anti-TNF antibodies. Surgical resection of obstructed areas or of severely involved portions of intestine and drainage of abscesses caused

31、 by fistulas are often required.2022-3-26克罗恩病小肠节段性病变特征模式图克罗恩病小肠节段性病变特征模式图2022-3-26溃疡性结肠炎溃疡性结肠炎（ Ulcerative Colitis ） 溃疡性结肠炎（溃疡性结肠炎（Ulcerative Colitis） 是结直肠发生的慢性浅表性炎症是结直肠发生的慢性浅表性炎症 Ulcerative Colitis is a Chronic Superficial Inflammation of the Colon and Rectum 临床表现慢性腹泻，直肠出血。是有加重和缓解，可伴有临床表现慢性腹泻，直肠出血。

32、是有加重和缓解，可伴有局部和全身并发症局部和全身并发症 Ulcerative colitis is characterized by chronic diarrhea and rectal bleeding, with a pattern of exacerbations and remissions and with the possibility of serious local and systemic complications.2022-3-26流行病学（流行病学（Epidemiology） In Europe and North America, the incidence of

33、ulcerative colitis is 4 to 7 per 100,000 population, and its prevalence is 40 to 80 per 100,000. It usually begins in early adult life, with a peak incidence in the third decade. However, it also occurs in childhood and old age. In the United States, whites are affected more commonly than blacks.202

34、2-3-26发病机制（发病机制（Pathogenesis）原因不清，可能与遗传相关原因不清，可能与遗传相关 The cause of ulcerative colitis is unknown. In some families as many as six patients with this disease have been described, and concordance has been reported in monozygotic twins. However, available family studies do not suggest any distinct mode

35、 of genetic transmission.自身免疫病机制自身免疫病机制 The possibility that an abnormal immune response may be involved has been studied extensively. There is abundant lymphoid tissue throughout the colon, and ulcerative colitis may occur with autoimmune-like conditions, such as uveitis, erythema nodosum, and vasc

36、ulitis. Increased circulating antibodies against antigens in colonic epithelial cells and against cross-reacting antigens in enterobacteria may occur. Antineutrophil cytoplasmic antibodies are found in 80% of patients with ulcerative colitis. However, these abnormalities are neither unique for ulcer

37、ative colitis, nor are they a prerequisite for the development of the disease.2022-3-26病理变化（Pathology）Ulcerative colitis is a diffuse disease. It usually extends from the most distal part of the rectum（远端直肠） for a variable distance proximally (Fig. 13-26). Sparing of the rectum or involvement of the

38、 right side of the colon alone is rare and suggests the possibility of another disorder, such as Crohn disease.Inflammation in ulcerative colitis is generally limited to the colon and rectum. It rarely involves the small intestine, stomach, or esophagus.Ulcerative colitis is essentially a mucosal di

39、sease. Deeper layers are uncommonly involved, mainly in fulminant cases and usually in association with toxic megacolon.2022-3-26三大主要病变三大主要病变Three major pathologic features characterize ulcerative colitis and help to differentiate it from other inflammatory conditions:Figure 13-26. Ulcerative coliti

40、s. Prominent erythema and ulceration of the colon begin in the ascending colon and are most severe in the rectosigmoid area.2022-3-26The following morphologic sequence may develop rapidly or over a course of years.EARLY COLITIS: Early in the evolution of the disease, the mucosal surface is raw, red,

41、 and granular. It is frequently covered with a yellowish exudate and bleeds easily. Later small, superficial erosions or ulcers may appear. These occasionally coalesce to form irregular, shallow, ulcerated areas that appear to surround islands of intact mucosa.The microscopic features of early ulcer

42、ative colitis include (1) mucosal congestion, edema, and microscopic hemorrhages; (2) a diffuse chronic inflammatory infiltrate in the lamina propria; and (3) damage and distortion of the colorectal crypts, which are often surrounded and infiltrated by neutrophils. Suppurative necrosis of the crypt

43、epithelium gives rise to the characteristic crypt abscess, which appears as a dilated crypt filled with neutrophils (Fig. 13-27).2022-3-26Figure 13-27. Ulcerative colitis. A. A full-thickness section of colon resected for ulcerative colitis shows inflammation affecting the mucosa with sparing of the

44、 submucosa and muscularis propria. B. Sections of a mucosal biopsy from a patient with active ulcerative colitis show expansion of the lamina propria and several crypt abscesses (arrows). C. Chronic ulcerative colitis shows significant crypt distortion and atrophy.2022-3-26 PROGRESSIVE COLITIS: As t

45、he disease continues, mucosal folds are lost. Lateral extension and coalescence of crypt abscesses can undermine the mucosa, leaving areas of ulceration adjacent to hanging fragments of mucosa. Such mucosal excrescences are termed inflammatory polyps. Granulation tissue develops in denuded areas. Im

46、portantly, the strictures characteristic of Crohn disease are absent. Microscopically, colorectal crypts may appear tortuous, branched, and shortened in the late stages, and the mucosa may be diffusely atrophic.2022-3-26 ADVANCED COLITIS: In long-standing cases, the large bowel is often shortened, e

47、specially in the left side. Mucosal folds are indistinct and are replaced by a granular or smooth mucosal pattern. Microscopically, advanced ulcerative colitis is characterized by mucosal atrophy and a chronic inflammatory infiltrate in the mucosa and superficial submucosa. Paneth metaplasia is comm

48、on.2022-3-26Clinical Features The clinical course and manifestations are very variable. Most patients (70%) have intermittent attacks, with partial or complete remission between attacks. A small number (10%) have a very long remission (several years) after their first attack. The remaining 20% have

49、continuous symptoms without remission.2022-3-26 MILD COLITIS: Half of patients with ulcerative colitis have mild disease. Their major symptom is rectal bleeding, sometimes accompanied by tenesmus (rectal pressure and discomfort). The disease in these patients is usually limited to the rectum but may

50、 extend to the distal sigmoid colon. Extraintestinal complications are uncommon, and in most patients in this category, disease remains mild throughout their lives.2022-3-26 MODERATE COLITIS: About 40% of patients have moderate ulcerative colitis. They usually have recurrent episodes of loose bloody

51、 stools, crampy abdominal pain, and frequently low-grade fever, lasting days or weeks. Moderate anemia is a common result of chronic fecal blood loss.2022-3-26 SEVERE COLITIS: About 10% of patients have severe or fulminant ulcerative colitis, often during a flare of activity. They may have more than

52、 6 and sometimes more than 20 bloody bowel movements daily, often with fever and other systemic manifestations. Blood and fluid loss rapidly leads to anemia, dehydration, and electrolyte depletion. Massive hemorrhage may be life-threatening. A particularly dangerous complication is toxic megacolon,

53、which is characterized by extreme dilation of the colon and an associated high risk for perforation. Fulminant ulcerative colitis is a medical emergency requiring immediate, intensive medical therapy, and, in some cases, prompt colectomy. About 15% of patients with fulminant ulcerative colitis die o

54、f the disease.2022-3-26The distinction between ulcerative colitis and Crohn colitis is based on different anatomical localization and histopathology (Table 13-1). The medical treatment of ulcerative colitis depends on the sites involved and the severity of the inflammation. The 5-aminosalicylate鈥揵as

55、ed compounds are the mainstays of treatment for patients with mild-to-moderate ulcerative colitis. Corticosteroids and immunosuppressive and immunoregulatory agents (azathioprine or mercaptopurine) are used in patients who have severe and refractory disease.2022-3-26Extraintestinal Manifestations Ar

56、thritis is seen in 25% of patients with ulcerative colitis. Eye inflammation (mostly uveitis) and skin lesions develop in about 10%. The most common cutaneous lesions are erythema nodosum and pyoderma gangrenosum; the latter is a serious, noninfective disorder characterized by deep, purulent, necrot

57、ic ulcers in the skin. Liver disease occurs in about 4% of patients, most commonly primary sclerosing cholangitis. Thromboembolic phenomena, usually deep vein thromboses of the lower extremities, occur in 6% of ulcerative colitis patients.2022-3-26Ulcerative Colitis and Colorectal Cancer People with

58、 long-standing ulcerative colitis have a higher risk of colorectal cancer than the general population. Colorectal epithelial dysplasia is a neoplastic epithelial proliferation and precursor to colorectal carcinoma in patients with long-term ulcerative colitis. High-grade epithelial dysplasia reflect

59、s a significant risk for the development of colorectal cancer, and when identified in a biopsy, it is a strong indication for colectomy.2022-3-26TABLE 13-1 Comparison of the Pathologic Features in the Colon of Crohn Disease and Ulcerative Colitis2022-3-26LesionCrohn DiseaseUlcerative ColitisMacrosco

60、pIcThickened bowel wallTypicalUncommonLuminal narrowingTypicalUncommon透壁性 lesionsCommonAbsentRight colon predominanceTypicalAbsentFissures and fistulasCommonAbsentCircumscribed ulcersCommonAbsentConfluent linear ulcersCommonAbsentPseudopolypsAbsentCommonMICROSCOPIcTransmural inflammationTypicalUncom