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Granulomatous Inflammation
肉芽腫性炎癥
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.
肉芽腫形態提示是一種無明顯不同的特定類型的慢性炎癥；它可以是分枝桿菌感染（加上其他一些細菌）、真菌感染、自身免疫性疾病、一些毒素或刺激物和結節病。肉芽腫分為壞死性（通常是感染性）和非壞死性。干酪樣肉芽腫是壞死性肉芽腫的同義詞，是壞死呈干酪樣外觀而命名的，通常意味著是結核病。
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).
肉芽腫的組織學表現為顯微鏡下組織細胞聚集，周圍有淋巴細胞和漿細胞。其表現為從少量組織細胞聚集（如克羅恩病；圖3.6）到大而境界清楚的細胞呈漩渦狀（結節?。粓D3.7），再到壞死碎片周圍的組織細胞層（肺結核、真菌；圖3.8）。巨細胞是有幫助的，但不是必需的。陳舊性肉芽腫可以變成透明狀和無細胞成分（圖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.
圖3.6：克羅恩病中的肉芽腫。這些結腸肉芽腫很小（箭頭所示），只有在高倍鏡下才能看到淡染的組織細胞。周圍有一圈淋巴細胞是很常見。
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.
圖3.7。結節病中的肉芽腫。這些肉芽腫通常比克羅恩病的肉芽腫更大而堅實，更容易識別。它們看起來像是清晰的粉紅色組織細胞團。偶爾出現多核巨細胞（箭頭）。
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).
圖3.8。結核病中干酪樣或壞死性肉芽腫。這些肉芽腫中的組織細胞只在周圍可見，因為中心是一團壞死和細胞碎片（箭頭）。
Figure 3.9. Hyalinized granuloma. The amorphous area of hyalinized collagen likely represents old, burned-out necrosis.
圖3.9。透明變肉芽腫。膠原透明樣變的無組織的區域像是陳舊性燒灼性壞死。
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染色呈亮粉紅色，格莫瑞六亞甲基四胺銀（GMS）染色呈黑色。對于這些大多數微生物，不僅要確定其存在和形態，而且要確定它是侵入活組織還是定植于壞死碎片區。大小有助于識別不同的酵母菌（圖3.10）。
Figure 3.10：Relative size of yeasts compared to an RBC (an RBC is approximately 7 um).
圖3.10：酵母菌與紅細胞大小的比較（紅細胞約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上呈圓形到卵圓形的酵母和假菌絲（有分段和無分枝）。它們經常出現在上皮表面的碎片中（圖3.11）。曲霉菌在HE上可見菌絲細長，有45°的分支和分隔。它們可能以實體真菌球或組織中的單個菌絲出現（圖3.12）。治療后的曲霉菌可能有不同的形態。
Figure 3.11. Candida. This example from the esophagus shows magenta pseudohyphae and yeasts (arrows, PAS stain).
圖3.11：這個病例的念珠菌來自食管，顯示為紫紅色假菌絲和酵母（箭頭，PAS染色）。
Figure 3.12. Aspergillus. A forest of branching hyphae is visible by GMS stain.
圖3.12：曲霉菌：GMS染色時可見一片的分枝菌絲。
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規則和無橫隔寬菌絲，呈彎曲樹枝狀，分枝點寬（圖3.13）。在HE上，它們幾乎是看不見的，因為它們在組織中基本上是寬且中間呈空心的。這些bread molds通常只見于中性粒細胞減少癥患者或有酮癥酸中毒的鼻竇炎患者。
Figure 3.13. Mucor. A PAS stain shows the thick, hollow, irregular outlines of Mucor (arrow).
圖3.13：毛霉菌。PAS染色顯示毛霉菌粗大、中空、不規則輪廓（箭頭）。
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).
組織胞漿菌是一種小的細胞內酵母，基芽窄，常位于巨噬細胞中。HE和Giemsa染色時，位于巨噬細胞中為纖細的2μm大小。然而，在透明肉芽腫中，銀染顯示的酵母大小接近紅細胞（約5μm；圖3.14）。
Figure 3.14. Histoplasma. Tiny yeasts are visible on GMS stain (40× objective).
圖3.14：組織胞漿菌。GMS染色可見微小的酵母（40×物鏡）。
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.
隱球菌通常是被包裹的酵母，基芽窄；一些可能在巨噬細胞中，但通常位于組織中；在GMS染色中，其大小不一，有些可能是塌陷壓扁的球形（圖3.15）。這種大小不一實際上是隱球菌的一個主要標志。隱球菌包膜染色可以與其他酵母菌區分，包括mucicarmine和Fontana- Masson。但是，要知道隱球菌偶爾無包膜。
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.
圖3.15：隱球菌。在（40×物鏡）顯微鏡下，GMS染色顯示隱球菌更大，且其大小和形狀不一。
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肺孢子蟲，原名卡氏肺孢子蟲，是一種酵母，因此GMS染色呈黑色。它們是在肺泡中發現的扁平的隱形眼鏡狀生物（圖3.16）。在HE上看不到，但通常伴有泡沫狀粉紅色滲出物/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.
圖3.16：肺孢子蟲病GMS染色（40×物鏡）。
Bacteria
細菌
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.
大多數細菌不能通過染色發現。這是因為，我們只能說“革蘭氏陽性球菌簇”，例如，如果沒有培養基，這是毫無用處的。有一些很難培養的細菌最好用染色來識別。
Figure 3.17. Mycobacteria on AFB stain. In this example, tiny wine-red rods are visible within the tissue (arrows) under the 40× objective.
圖3.17：本例AFB染色的分枝桿菌，40× 物鏡下的組織（箭頭）內可見微小的酒紅色棒狀物。
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.
壞死性肉芽腫是分枝桿菌（引起結核病和其他疾病）的組織學證據。在HE上看不到這種生物，在免疫能力強的病人中可能非常稀少。傳統染色方法是抗酸（AFB）染色法，這種染色法使組織不著色，某些細胞類型偶爾為淡粉紅色，但分枝桿菌染色為明亮的酒紅色（圖3.17）。這些微小的散在的細菌；你至少需要20倍才能發現它們。在40× 的鏡下掃描整個玻片，雖然是痛苦的，但必須排除感染。如果臨床高度懷疑，但AFB染色為陰性，金胺羅丹明是一種對結核病更敏感的熒光染色劑，但需要熒光顯微鏡觀察。
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，禽流感分枝桿菌（MAI）引起感染。在這些患者中，分枝桿菌被巨噬細胞吞噬，然后在細胞內瘋狂繁殖，形成泡沫樣巨噬細胞。在十二指腸中，這可能看起來像惠普爾?。╓hipple’s病），PAS染色可區分兩者（惠普爾病中具有越橘的組織細胞存在，但在MAI感染時為細桿狀）。MAI抗酸（AFB）染色也呈陽性。
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).
幽門螺桿菌是胃潰瘍最常見的病因。組織學上，你應該看到胃慢性炎癥浸潤，零散的一些活動性炎癥（中性粒細胞）。胃竇感染更為常見。用Diff-Quik或Giemsa染色，觀察活動性炎癥區域。如果存在，幽門螺桿菌將以微小的（20×時幾乎看不到的）海鷗形桿菌簇的形式位于小凹或表面（圖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.
圖3.18。幽門螺桿菌。如圖所示（箭頭），HE染色可在胃黏膜小凹處看到該桿菌。
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).
放線菌可形成一個泡芙球菌落，在扁桃體中是完全不明顯的，但在子宮內膜，特別是在宮內節育器的設置中卻很重要。HE外觀為顆粒狀灰紫色云，有時呈絲狀，無可識別的細胞或結構（圖3.19）。
Figure 3.19. Actinomyces. This filamentous ball of organisms is easily overlooked, as it resembles fibrin.
圖3.19：放線菌。這種絲狀的生物體球很容易被忽略，因為它類似于纖維蛋白。
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.
作為一個有趣的歸納，DNA病毒（HSV、CMV、水痘、腺病毒、JC和BK病毒、HPV和痘病毒）往往對細胞核造成明顯的病毒性細胞病變。RNA病毒則沒有。
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).
單純皰疹病毒（HSV）容易引起廣泛的組織損傷和潰瘍。它會感染上皮細胞，所以觀察潰瘍附近的細胞。細胞變成多核，轉化后的細胞核相互形成。染色質完全被玻璃狀的核包涵體（病毒蛋白）所取代，由殘留染色質的暗邊勾勒出來，就好像核是從內部被消化一樣（圖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).
圖3.20：皰疹感染。典型的核改變包括多個核，周圍有染色質邊緣，玻璃狀的核包涵體幾乎替換了染色質（箭頭）。
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.
巨細胞病毒（CMV）也可引起潰瘍，但感染組織可能無明顯的局部損傷。它感染上皮細胞、內皮細胞和間充質細胞。如果是潰瘍，看潰瘍處，而不是周圍。這種病毒使細胞核增大。細胞核有一個非常特征性的包涵體；一個暗密的圓形/卵圓形包涵體，周圍有一個淡淡的光暈，全部在核膜內（圖3.21）。淡的光暈并不總是完全可見的，所以在一組非腫瘤細胞中發現大的暗核時，你應考慮到CMV。免疫染色有幫助。
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.
圖3.21：巨細胞病毒感染。胃腸道的內皮細胞（箭頭）顯示典型的巨細胞病毒核改變，中央有一個紅色致密的核包涵體，周圍有一個清晰的光暈和邊緣的紫色染色質。
文中如有錯誤，謝謝指正！
