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Granulomatous Inflammation
肉芽肿性炎症
A granulomatous appearance indicates a specific type of chronic inflammation with a limited differential; it can indicate mycobacterial infection (plus a few other bacteria), fungal infection, autoimmune disease, some toxins or irritants, and sarcoidosis. Granulomas are divided into necrotizing (usually infectious) and non-necrotizing. Caseating granulomas are synonymous with necrotizing granulomas, named after the cheese-like gross appearance of the necrosis, and usually implying tuberculosis.
肉芽肿形态提示是一种无明显不同的特定类型的慢性炎症；它可以是分枝杆菌感染（加上其他一些细菌）、真菌感染、自身免疫性疾病、一些毒素或刺激物和结节病。肉芽肿分为坏死性（通常是感染性）和非坏死性。干酪样肉芽肿是坏死性肉芽肿的同义词，是坏死呈干酪样外观而命名的，通常意味着是结核病。
The histologic appearance of a granuloma is a microscopic aggregate of histiocytes, with surrounding lymphocytes and plasma cells. The appearance ranges from tiny collections of histiocytes (as in Crohn’s disease; Figure 3.6) to large well-circumscribed whorls of cells (sarcoidosis; Figure 3.7), to a layer of histiocytes surrounding a pool of necrotic debris (tuberculosis, fungus; Figure 3.8). Giant cells are helpful but not essential. Old granulomas can become hyalinized and acellular (Figure 3.9).
肉芽肿的组织学表现为显微镜下组织细胞聚集，周围有淋巴细胞和浆细胞。其表现为从少量组织细胞聚集（如克罗恩病；图3.6）到大而境界清楚的细胞呈漩涡状（结节病；图3.7），再到坏死碎片周围的组织细胞层（肺结核、真菌；图3.8）。巨细胞是有帮助的，但不是必需的。陈旧性肉芽肿可以变成透明状和无细胞成分（图3.9）。
Figure 3.6. Granulomas in Crohn’s disease. These granulomas of the colon are subtle (arrow), and the pale histiocytes may be seen only on high power. A surrounding collar of lymphocytes is common.
图3.6：克罗恩病中的肉芽肿。这些结肠肉芽肿很小（箭头所示），只有在高倍镜下才能看到淡染的组织细胞。周围有一圈淋巴细胞是很常见。
Figure 3.7. Granulomas in sarcoid. These granulomas are often more substantial and more easily recognized than those in Crohn’s disease. They appear as well-defined masses of pink histiocytes. Occasional multinucleated giant cells (arrowhead) are present.
图3.7。结节病中的肉芽肿。这些肉芽肿通常比克罗恩病的肉芽肿更大而坚实，更容易识别。它们看起来像是清晰的粉红色组织细胞团。偶尔出现多核巨细胞（箭头）。
Figure 3.8. Caseating or necrotizing granulomas in tuberculosis. The histiocytes in these granulomas are visible only at the periphery, as the center is a mass of necrosis and cellular debris (arrow).
图3.8。结核病中干酪样或坏死性肉芽肿。这些肉芽肿中的组织细胞只在周围可见，因为中心是一团坏死和细胞碎片（箭头）。
Figure 3.9. Hyalinized granuloma. The amorphous area of hyalinized collagen likely represents old, burned-out necrosis.
图3.9。透明变肉芽肿。胶原透明样变的无组织的区域像是陈旧性烧灼性坏死。
Specific Organisms and Their Stains
特殊微生物及其染色
Fungi
真菌
Fungal organisms stain bright pink on periodic acid-Schiff (PAS) stain and black on Gomori’s methenamine silver (GMS) stain. For most of these organisms, it is important to identify not just the presence and morphology of the organism but whether it is invading viable tissue or colonizing necrotic debris. Size can be helpful in identifying the various yeasts (Figure 3.10).
真菌用PAS染色呈亮粉红色，格莫瑞六亚甲基四胺银（GMS）染色呈黑色。对于这些大多数微生物，不仅要确定其存在和形态，而且要确定它是侵入活组织还是定植于坏死碎片区。大小有助于识别不同的酵母菌（图3.10）。
Figure 3.10：Relative size of yeasts compared to an RBC (an RBC is approximately 7 um).
图3.10：酵母菌与红细胞大小的比较（红细胞约7μm）。
Candida are visible on H&E as round-to-oval yeast forms and pseudohyphae (segmented and nonbranching). They are often found in the debris at the epithelial surface (Figure 3.11). Aspergilli are visible on H&E as long, thin hyphae with 45° branching and septations. They may appear as a solid fungal ball or as single hyphae in the tissue (Figure 3.12). Treated Aspergilli may have different morphology.
念珠菌在HE上呈圆形到卵圆形的酵母和假菌丝（有分段和无分枝）。它们经常出现在上皮表面的碎片中（图3.11）。曲霉菌在HE上可见菌丝细长，有45°的分支和分隔。它们可能以实体真菌球或组织中的单个菌丝出现（图3.12）。治疗后的曲霉菌可能有不同的形态。
Figure 3.11. Candida. This example from the esophagus shows magenta pseudohyphae and yeasts (arrows, PAS stain).
图3.11：这个病例的念珠菌来自食管，显示为紫红色假菌丝和酵母（箭头，PAS染色）。
Figure 3.12. Aspergillus. A forest of branching hyphae is visible by GMS stain.
图3.12：曲霉菌：GMS染色时可见一片的分枝菌丝。
Mucor and zygomycetes have irregular and wide nonseptate hyphae and have the appearance of gnarled tree branch outlines with wide branch points (Figure 3.13). On H&E, they can be almost invisible, as they are essentially wide hollow spaces in the tissue. These are the bread molds and are typically seen only in very neutropenic patients or in sinusitis in a patient with ketoacidosis.
毛霉菌和接合菌有不规则和无横隔宽菌丝，呈弯曲树枝状，分枝点宽（图3.13）。在HE上，它们几乎是看不见的，因为它们在组织中基本上是宽且中间呈空心的。这些bread molds通常只见于中性粒细胞减少症患者或有酮症酸中毒的鼻窦炎患者。
Figure 3.13. Mucor. A PAS stain shows the thick, hollow, irregular outlines of Mucor (arrow).
图3.13：毛霉菌。PAS染色显示毛霉菌粗大、中空、不规则轮廓（箭头）。
Histoplasma are tiny intracellular yeast forms with narrow-based budding, often seen in macrophages. On H&E and Giemsa stain, these are delicate 2-μm forms in macrophages. In a hyalinized granuloma, however, a silver stain shows distinct yeasts that are nearly the size of red cells (about 5 μm; Figure 3.14).
组织胞浆菌是一种小的细胞内酵母，基芽窄，常位于巨噬细胞中。HE和Giemsa染色时，位于巨噬细胞中为纤细的2μm大小。然而，在透明肉芽肿中，银染显示的酵母大小接近红细胞（约5μm；图3.14）。
Figure 3.14. Histoplasma. Tiny yeasts are visible on GMS stain (40× objective).
图3.14：组织胞浆菌。GMS染色可见微小的酵母（40×物镜）。
Cryptococcus are usually encapsulated yeast forms with narrow-based budding; some may be in macrophages but are often free in the tissue; on GMS the sizes are variable, and some may collapse into squashed balls (Figure 3.15). This variability in size is actually a key indicator of Cryptococcus. Stains for the capsule of Cryptococcus can differentiate it from other yeasts, including mucicarmine and Fontana-Masson. However, be aware that Cryptococcus can occasionally lose the capsule.
隐球菌通常是被包裹的酵母，基芽窄；一些可能在巨噬细胞中，但通常位于组织中；在GMS染色中，其大小不一，有些可能是塌陷压扁的球形（图3.15）。这种大小不一实际上是隐球菌的一个主要标志。隐球菌包膜染色可以与其他酵母菌区分，包括mucicarmine和Fontana- Masson。但是，要知道隐球菌偶尔无包膜。
Figure 3.15. Cryptococcus. This photograph is taken at the same magnification as Figure 3.14.The organisms are significantly larger and show a range of sizes and shapes on GMS stain.
图3.15：隐球菌。在（40×物镜）显微镜下，GMS染色显示隐球菌更大，且其大小和形状不一。
Pneumocystis jirovecii, formerly known as Pneumocystis carinii, is a yeast and therefore black on GMS. They are flattened contact-lens-shaped organisms found in the alveoli (Figure 3.16). They are not visible on H&E but are usually accompanied by a foamy pink exudate.
Jirovecii肺孢子虫，原名卡氏肺孢子虫，是一种酵母，因此GMS染色呈黑色。它们是在肺泡中发现的扁平的隐形眼镜状生物（图3.16）。在HE上看不到，但通常伴有泡沫状粉红色渗出物/分泌物。
Figure 3.16. Pneumocystis. This photograph in the lung is taken at the same power as Figures 3.14 and 3.15. The organisms are stained with GMS stain.
图3.16：肺孢子虫病GMS染色（40×物镜）。
Bacteria
细菌
Most bacteria are not found by, or identified with, stains. This is because there is little more we could say than “Gram-positive cocci in clusters,” for example, which is pretty unhelpful without a culture. There are a few that are hard to culture and are best identified by stains.
大多数细菌不能通过染色发现。这是因为，我们只能说“革兰氏阳性球菌簇”，例如，如果没有培养基，这是毫无用处的。有一些很难培养的细菌最好用染色来识别。
Figure 3.17. Mycobacteria on AFB stain. In this example, tiny wine-red rods are visible within the tissue (arrows) under the 40× objective.
图3.17：本例AFB染色的分枝杆菌，40× 物镜下的组织（箭头）内可见微小的酒红色棒状物。
Necrotizing granulomas are histologic evidence of Mycobacterium (causing tuberculosis and other diseases). The organisms are not seen on H&E and may be very sparse in an immunocompetent patient. The conventional stain is the acid-fast bacilli (AFB) stain, which leaves the tissue unstained, with occasional pink blush in some cell types, but stains mycobacteria a bright wine red (Figure 3.17). These are tiny scattered bacilli; you need to be at 20×, at least, to spot them. Scanning the entire slide at 40× for red lint is painful but necessary to rule out infection. If clinical suspicion is high but an AFB is negative, an auramine-rhodamine is a more sensitive fluorescent stain for tuberculosis, but requires a fluorescent microscope for viewing.
坏死性肉芽肿是分枝杆菌（引起结核病和其他疾病）的组织学证据。在HE上看不到这种生物，在免疫能力强的病人中可能非常稀少。传统染色方法是抗酸（AFB）染色法，这种染色法使组织不着色，某些细胞类型偶尔为淡粉红色，但分枝杆菌染色为明亮的酒红色（图3.17）。这些微小的散在的细菌；你至少需要20倍才能发现它们。在40× 的镜下扫描整个玻片，虽然是痛苦的，但必须排除感染。如果临床高度怀疑，但AFB染色为阴性，金胺罗丹明是一种对结核病更敏感的荧光染色剂，但需要荧光显微镜观察。
Mycobacterium avium-intracellulare (MAI) causes infection in an immuno-compromised patient. In these patients, the mycobacteria are eaten by macrophages and then multiply like crazy within the cells, giving the appearance of foamy macrophages. In the duodenum, this can look just like Whipple’s disease, but a PAS stain will differentiate the two (histiocytes stuffed with cranberries in Whipple’s disease but with fine rods in MAI infection). An AFB stain will also be positive in MAI.
在免疫功能低下的患者中，禽流感分枝杆菌（MAI）引起感染。在这些患者中，分枝杆菌被巨噬细胞吞噬，然后在细胞内疯狂繁殖，形成泡沫样巨噬细胞。在十二指肠中，这可能看起来像惠普尔病（Whipple’s病），PAS染色可区分两者（惠普尔病中具有越橘的组织细胞存在，但在MAI感染时为细杆状）。MAI抗酸（AFB）染色也呈阳性。
Helicobacter pylori is the most common cause of gastric ulcers. Histologically you should see a chronic inflammatory infiltrate in the stomach, with a little activity here and there (neutrophils). Infection is more common in the antrum. On Diff-Quik or Giemsa stain, look in the areas of activity. If present, H. pylori will be in the pit lumens or at the surface in clusters of tiny (barely visible at 20×) seagull-shaped bacilli (Figure 3.18).
幽门螺杆菌是胃溃疡最常见的病因。组织学上，你应该看到胃慢性炎症浸润，零散的一些活动性炎症（中性粒细胞）。胃窦感染更为常见。用Diff-Quik或Giemsa染色，观察活动性炎症区域。如果存在，幽门螺杆菌将以微小的（20×时几乎看不到的）海鸥形杆菌簇的形式位于小凹或表面（图3.18）。
Figure 3.18. Helicobacter pylori. The bacilli may be visible on H&E stain, as seen here (arrows), in the pits of the gastric mucosa.
图3.18。幽门螺杆菌。如图所示（箭头），HE染色可在胃黏膜小凹处看到该杆菌。
Actinomyces, causing a puffball bacterial colony, is completely unremarkable in the tonsil but significant in endometrium, especially in the setting of an intrauterine device. The H&E appearance is a granular grey-purple cloud, sometimes filamentous, with no identifiable cells or structures (Figure 3.19).
放线菌可形成一个泡芙球菌落，在扁桃体中是完全不明显的，但在子宫内膜，特别是在宫内节育器的设置中却很重要。HE外观为颗粒状灰紫色云，有时呈丝状，无可识别的细胞或结构（图3.19）。
Figure 3.19. Actinomyces. This filamentous ball of organisms is easily overlooked, as it resembles fibrin.
图3.19：放线菌。这种丝状的生物体球很容易被忽略，因为它类似于纤维蛋白。
Viruses
病毒
As an interesting generalization, DNA viruses (HSV, CMV, varicella, adenovirus, JC and BK virus, HPV, and the poxviruses) tend to cause visible viral cytopathic effects on the cell nucleus. The RNA viruses do not.
作为一个有趣的归纳，DNA病毒（HSV、CMV、水痘、腺病毒、JC和BK病毒、HPV和痘病毒）往往对细胞核造成明显的病毒性细胞病变。RNA病毒则没有。
Herpes simplex virus (HSV) tends to cause extensive tissue damage and ulcers. It infects the epithelium, so look in the cells immediately adjacent to the ulcer. The cells become multinucleated, with the transformed nuclei molding into each other. The chromatin is entirely displaced by glassy nuclear inclusions (viral proteins), outlined by a dark rim of residual chromatin, as though the nucleus is being digested from the inside (Figure 3.20).
单纯疱疹病毒（HSV）容易引起广泛的组织损伤和溃疡。它会感染上皮细胞，所以观察溃疡附近的细胞。细胞变成多核，转化后的细胞核相互形成。染色质完全被玻璃状的核包涵体（病毒蛋白）所取代，由残留染色质的暗边勾勒出来，就好像核是从内部被消化一样（图3.20）。
Figure 3.20. Herpes infection. The classic nuclear changes include multiple molded nuclei with a peripheral rim of chromatin and a glassy inclusion nearly replacing the chromatin (arrow).
图3.20：疱疹感染。典型的核改变包括多个核，周围有染色质边缘，玻璃状的核包涵体几乎替换了染色质（箭头）。
Cytomegalovirus (CMV) can also cause ulcers but may infect tissue without obvious localizing damage. It infects epithelial, endothelial, and mesenchymal cells. In the case of an ulcer, look in the ulcer bed, not the periphery. The virus causes enlarged cells with large nuclei. The nuclei have a very characteristic inclusion; a dark dense round/oval inclusion surrounded by a pale halo, all within the nuclear membrane (Figure 3.21). The pale halo is not always entirely visible, so finding large smudgy dark nuclei in a group of non-neoplastic cells should prompt you to consider CMV. Immunostains help.
巨细胞病毒（CMV）也可引起溃疡，但感染组织可能无明显的局部损伤。它感染上皮细胞、内皮细胞和间充质细胞。如果是溃疡，看溃疡处，而不是周围。这种病毒使细胞核增大。细胞核有一个非常特征性的包涵体；一个暗密的圆形/卵圆形包涵体，周围有一个淡淡的光晕，全部在核膜内（图3.21）。淡的光晕并不总是完全可见的，所以在一组非肿瘤细胞中发现大的暗核时，你应考虑到CMV。免疫染色有帮助。
Figure 3.21. CMV infection. This endothelial cell in the gastrointestinal tract (arrow) shows the typical nuclear changes of CMV, with a central reddish dense nuclear inclusion, surrounded by a clear halo and a rim of purple chromatin.
图3.21：巨细胞病毒感染。胃肠道的内皮细胞（箭头）显示典型的巨细胞病毒核改变，中央有一个红色致密的核包涵体，周围有一个清晰的光晕和边缘的紫色染色质。
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