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(BQ) Part 2 book Pathology of infectious diseases presentation of content: Anaerobic bacterial infections; rickettsia, ehrlichia, and anaplasma infections; tuberculosis and infections by nontuberculous mycobacteria, buruli ulcer, dematiaceous fungal infections, parasitic infections,... and other contents.
16 Bacterial Gastrointestinal Infections ■■ Laura W Lamps Enteric pathogens are the leading cause of childhood death in the world and the second leading cause of death for people of all ages (second only to cardiovascular disease) In many areas of the world, problems with water quality, sanitation, and food hygiene practice contribute to the transmission of gastrointestinal infectious diseases Many other aspects of modern living also contribute to the transmission of enteric pathogens, however, including camping and water sports involving untreated water sources; poor swimming pool hygiene; frequent consumption of restaurant-prepared and prepackaged foods; more widespread consumption of raw or poorly cooked meats and seafood; and travel, particularly from an area of good sanitation to one of poor sanitation The number of bone marrow and solid organ transplant patients continues to increase as well, as does the population of patients with other immunocompromising conditions For all of these reasons, and as global urbanization, immigration, and transcontinental travel become more frequent, infectious diseases that were once limited to certain populations or regions of the world can now be found almost anywhere The goals of the surgical pathologist in evaluating gastrointestinal specimens for infection are basically twofold First, the surgical pathologist must attempt to differentiate histologic changes suggesting infection from other inflammatory processes, including chronic idiopathic inflammatory bowel disease (ulcerative colitis or Crohn disease), ischemia, adverse drug reactions, and autoimmune disorders Following this determination, dedicated attempts must be made to diagnose the specific infectious organism The surgical pathologist’s ability to detect infectious processes in tissue sections has grown exponentially with the advent of new histochemical and immunohistochemical stains, as well as molecular assays As these techniques have developed and become more widely available for diagnostic use, our knowledge of the pathologic spectrum that specific infectious organisms can cause has also grown, including our knowledge of those infections that can closely mimic other inflammatory processes ■■ HELICOBACTER SPECIES AND RELATED SEQUELAE HELICOBACTER PYLORI Helicobacter pylori (HP) is a gram-negative bacterium that infects the stomach Although the incidence of H pylori infection is decreasing, in part due to eradication, it remains one of the most common bacterial infections worldwide Infection is associated with many gastrointestinal diseases, including chronic gastritis, atrophic gastritis, peptic ulcers, gastric adenocarcinoma, and lymphomas of the mucosa-associated lymphoid tissue (MALT) type However, the exact mechanisms by which HP cause disease remain unclear C linical F eatures Patients with H pylori-associated gastritis may present with dyspepsia, epigastric pain, nausea, vomiting, and gastrointestinal (GI) bleeding Many infected patients are asymptomatic, however H PYLORI—FACT SHEET Definition ■ Gram-negative bacterium that infects the stomach Location ■ Stomach, most frequently the antrum Clinical Features ■ Dyspepsia, epigastric pain, nausea, vomiting, and GI bleeding; many patients are asymptomatic Treatment ■ Antibiotics, proton-pump inhibitors 297 298 P athologic F eatures Gross Findings Mucosal changes are nonspecific and include erythema, mucosal granularity, and abnormal vascular pattern Nodularity of the mucosa may be seen, especially in children, and may correlate with lymphoid hyperplasia The antrum is most commonly affected, although the fundic and cardiac mucosa also are frequently involved In general, there is poor correlation between endoscopic findings and the presence or severity of histologic findings A PATHOLOGY OF INFECTIOUS DISEASES Microscopic Findings The inflammatory pattern most commonly associated with HP infection is chronic, active gastritis, featuring a mononuclear cell infiltrate in the lamina propria that is rich in plasma cells, along with neutrophils that may infiltrate the glandular epithelium (Figure 16-1A-C) Scattered eosinophils are also common Lymphoid aggregates are a frequent feature Significant intraepithelial lymphocytosis may be seen as well The severity of the inflammation often does not correlate with the number of organisms found HP is rarely seen overlying areas of intestinal metaplasia B C FIGURE 16-1 Helicobacter pylori–associated chronic active gastritis The lamina propria is expanded by a predominantly plasmacytic infiltrate (A-C), with neutrophilic infiltration of the glands (C) Lymphoid aggregates are common (B) 299 CHAPTER 16 Bacterial Gastrointestinal Infections H PYLORI—PATHOLOGIC FEATURES Gross Findings ■ Erythema, granularity, abnormal vascular pattern, nodularity Microscopic Findings ■ Plasmacytic infiltrate in the lamina propria ■ Neutrophils that infiltrate the glandular epithelium ■ Lymphoid aggregates ■ Basophilic, spirillar, “seagull”-shaped organisms in mucus layer Differential Diagnosis ■ Autoimmune gastritis ■ Gastric Crohn disease ■ Lymphocytic gastritis associated with celiac disease ■ MALT lymphoma A ncillary S tudies FIGURE 16-2 Helicobacter pylori are present within mucin at the surface of the glands and in the pits and have a “seagull” or “comma” shape (H pylori immunostain) Helicobacter pylori are tiny (2 to 5 μ), slightly basophilic, spirillar, “comma”- or “seagull”-shaped organisms that are present in the mucus layer at the surface of the epithelium (Figure 16-2) They reside both at the luminal surface and in the pits; invasive organisms are seldom seen The distribution of HP may be very focal and patchy Under suboptimal conditions, the usually spirillar bacteria may undergo transformation to coccoid forms (Figure 16-3) that closely resemble mucus droplets, nonpathogenic bacteria, or other organisms such as fungal spores or coccidians Although the precise clinical significance of coccoid forms is uncertain, they are usually associated with spirillar forms, and the diagnosis of HP infection when only coccoid forms are present should be entertained with caution Useful histochemical stains include Giemsa, DiffQuik, and silver impregnation stains such as the Warthin-Starry or Steiner The latter may be combined with hematoxylin and eosin (H&E) and alcian blue (pH 2.5) to produce the popular “triple” or “Genta” stain that also allows for evaluation of gastric morphology (Figure 16-4) Silver impregnation stains are expensive and technically more difficult to obtain, but the bacteria are easy to identify using this method as they stain dark black and appear thicker Gram stain and the fluorescent acridine orange stain also will detect HP, although these are not routinely used The more recently introduced immunostain (Figure 16-5) has gained popularity due to the ease of identification and the specificity However, the immunostain may cross-react with other Helicobacter species (discussed later) Urease tests (such as the Campylobacter-like organism [CLO] test) are rapid, inexpensive, and have sensitivity and specificity comparable to histology Breath tests measuring excretion of carbon isotopes are quick, accurate (as a positive result indicates active infection), and noninvasive, but they are expensive, not widely available, and there is a slight radiation exposure with some methods Serologic studies have excellent sensitivity and specificity, and are inexpensive A positive result in the absence of treatment implies current infection; however, positive serologic studies may persist for quite some time following eradication of the bacteria Molecular detection assays also exist, but they are not widely available Culture of the organism is extremely difficult and is most commonly used when antibiotic susceptibility testing is needed D ifferential D iagnosis The differential diagnosis primarily includes other causes of nonerosive, nonspecific gastritis, including autoimmune gastritis, Crohn disease, infectious gastroenteritis, adverse drug reaction, and the lymphocytic gastritis associated with celiac disease If there is a particularly dense inflammatory infiltrate, H pylori–related gastritis must be distinguished from MALT lymphoma Architectural destruction, infiltration of lymphocytes into the submucosa, and numerous lymphoepithelial lesions favor a neoplastic process (Figure 16-6A and B), but gene rearrangement studies may be required to confirm the diagnosis Helicobacter pylori must be distinguished from contaminating oropharyngeal flora, which also may stain on nonspecific histochemical stains, by the morphology of the organism It must also be distinguished from other less common Helicobacter species (discussed later) 300 PATHOLOGY OF INFECTIOUS DISEASES FIGURE 16-3 Coccoid forms are highlighted on this H pylori immunostain FIGURE 16-4 The “Genta” or triple stain combines H&E, Alcian blue, and silver impregnation stains to highlight both black-staining H pylori at the luminal surface and gastric morphology (Genta stain, case courtesy of Dr Rodger Haggitt.) FIGURE 16-5 Helicobacter pylori immunostain highlights numerous organisms at the luminal surface 301 CHAPTER 16 Bacterial Gastrointestinal Infections A B FIGURE 16-6 Gastric MALT lymphoma A, This lowpower view shows effacement of the normal gastric architecture by a dense infiltrate of small lymphocytes B, Prominent lymphoepithelial lesions are easily identified HELICOBACTER HEILMANNII THERAPY Standard therapy consists of omeprazole and two antibiotics, usually clarithromycin and amoxicillin Helicobacter heilmannii (HH), a less commonly encountered Helicobacter species formerly known as Gastrospirillum hominis, is associated with animal contact Coinfection with HP and HH has been well documented C linical F eatures Symptoms are similar to those for HP, and both children and adults can be affected Helicobacter heilmannii infection has been associated rarely with ulcer formation, particularly in the context of nonsteroidal antiinflammatory drug use P athologic F eatures Infection is usually restricted to the antrum The morphologic features are indistinguishable from HP-associated gastritis, but they are often more focal, less severe, and involve fewer organisms Intestinal metaplasia, gastric adenocarcinoma, and MALT lymphoma are less commonly associated with HH H heilmannii is longer (4 to 10 μ in length) and more tightly spiraled than HP (Figure 16-7A, B) 302 PATHOLOGY OF INFECTIOUS DISEASES H HEILMANNII—FACT SHEET A Definition ■ Gram-negative bacterium that infects the stomach Location ■ Usually limited to the antrum Clinical Features ■ Similar to H pylori infection; only rarely associated with ulcers Treatment ■ Antibiotics, proton-pump inhibitors B H HEILMANNII—PATHOLOGIC FEATURES Gross Findings ■ Same as HP infection Microscopic Findings ■ Same as HP infection but more focal, fewer organisms Differential Diagnosis ■ H pylori A ncillary S tudies Helicobacter heilmannii is detectable by the same histochemical stains used for HP, and it is also immunopositive for the anti–H pylori immunohistochemical stains D ifferential D iagnosis The differential diagnosis primarily includes HPassociated gastritis P rognosis and T herapy Treatment is similar to that for H pylori ■■ BACTERIAL ENTERIC PATHOGENS Diarrhea due to bacterial infection is a significant worldwide health problem Escherichia coli, Salmonella, Shigella, and Campylobacter are the most commonly identified pathogens, and many bacterial infections of the gut are related to ingestion of contaminated water or food, or travel to foreign countries Although bacteria are often recovered by culture, surgical pathologists may play a valuable role in diagnosis FIGURE 16-7 Helicobacter heilmannii are longer than H pylori, with a tightly wound “corkscrew” shape (A, Courtesy of Dr Amy Hudson B, Modified triple stain, courtesy of Dr Dhanpat Jain.) Most enteric infections are self-limited Patients who undergo endoscopic evaluation and biopsy generally have unusual clinical features such as chronic or debilitating diarrhea, evidence of systemic disease, or a history of immunocompromise One of the most valuable (and least expensive) diagnostic aids for the surgical pathologist is a discussion with the gastroenterologist regarding specific symptoms, colonoscopic findings, travel history, food intake history (such as sushi or poorly cooked beef), sexual practices, and immune status Despite the large number of infectious agents that may affect the colon, the histologic features that they produce may be generally categorized as follows, and a general classification of colonic bacterial infections by histologic pattern is given in Table 16-1: Organisms producing very mild or no histologic changes (such as enteroadherent E coli or toxigenic V cholerae O1) E coli (+/− increased plasma cells) Syphilis C difficile Campylobacter Focal or mild: Shigella Salmonella typhimurium Marked: Architectural Distortion Occasionally typhimurium Salmonella LGV Predominantly Lymphohistiocytic Neisseria species MAI (immunocompromised patients Whipple’s disease Rhodococcus equi Diffuse Histiocytic Aeromonas MAI (immunocompetent patients) Actinomycosis M tuberculosis Yersinia Predominantly Granulomatous Other Vibrio species Shigella Occasionally C difficile Enterohemorrhagic E coli Pseudomembranous Pattern Spirochetosis Occasionally Aeromonas Campylobacter Shigella Acute Self-Limited Colitis Pattern Salmonella (especially nontyphoid) Enteroadherent E coli Enteropathogenic Toxigenic Vibrio cholerae O1 Minimal or No Inflammatory Change Classification of bacterial infections of the gastrointestinal tract by histologic pattern TABLE 16-1 C difficile Enterohemorrhagic E coli Ischemic Pattern CHAPTER 16 Bacterial Gastrointestinal Infections 303 304 PATHOLOGY OF INFECTIOUS DISEASES TABLE 16-2 Enteric bacterial infectious mimics of chronic idiopathic inflammatory bowel disease and ischemic colitis Mimics of Crohn Disease Mimics of Ulcerative Colitis Mimics of Ischemic Colitis Salmonella typhimurium Shigella species Enterohemorrhagic E coli Shigella species Nontyphoid Salmonella species C difficile (pseudomembranous colitis) Yersinia Aeromonas species C perfringens M tuberculosis Campylobacter (rarely) Aeromonas species Lymphogranuloma venereum Campylobacter (rarely) Lymphogranuloma venereum Organisms producing the histologic features of acute infectious type/self-limited colitis (AITC) or focal active colitis (FAC); many bacterial infections are in this category, including Campylobacter, Aeromonas, and some Salmonella species Organisms producing suggestive or diagnostic histologic features, such as pseudomembranes or granulomas Surgical pathologists should also be aware of the infections that are most likely to mimic other inflammatory bowel diseases, particularly Crohn disease, ulcerative colitis, and ischemic colitis (Table 16-2) FIGURE 16-8 Acute infectious-type colitis pattern in a case of Campylobacter colitis Note diffuse cryptitis, neutrophilic infiltrate in the lamina propria, and preservation of crypt architecture A cute S elf -L imited C olitis P attern or A cute I nfectious -T ype The acute infectious-type colitis (AITC) pattern, also known as the acute self-limited colitis (ASLC) pattern, is one of the patterns most commonly seen in enteric infections Because infections are not always self-limited and may even be fatal, many pathologists and clinicians prefer the essentially synonymous term acute infectious-type colitis The characteristic findings in AITC can be summarized as cryptitis in a background of preserved crypt architecture (Figure 16-8) Other characteristic findings include 305 CHAPTER 16 Bacterial Gastrointestinal Infections neutrophils in the lamina propria, crypt abscesses, crypt rupture, edema, and surface epithelial damage with superficial mucosal erosion The acute inflammatory component is often most prominent in the mid- to upper levels of the crypts The inflammatory changes may be focal or diffuse The lamina propria may contain increased mononuclear cells as well as neutrophils, but basal plasma cells should not be present Histologic changes of chronicity are usually present even in the initial biopsy specimen in patients with chronic idiopathic inflammatory bowel disease (CIIBD), and the lack of features of chronicity (crypt distortion, Paneth cell metaplasia, and basal lymphoplasmacytosis) helps to distinguish AITC from CIIBD Further c omplicating this issue is that many enteric pathogens may cause exacerbations or relapses of CIIBD, producing a histologically confusing picture; this reinforces the necessity of a diligent search for pathogens (including stool cultures) even in patients with the established diagnosis of CIIBD F ocal A ctive C olitis Focal active colitis (FAC) is the term that should be used to describe focal neutrophilic crypt injury (Figure 16-9) The spectrum of morphologic changes encompassed by the term FAC ranges from a single crypt abscess or focus of cryptitis to multiple foci of neutrophilic cryptitis or crypt abscesses within one or more large bowel biopsies Infection, particularly resolving infection, is the most common underlying cause of FAC (discussed later), although adverse drug reaction, bowel prep injury, and Crohn disease (particularly in children) also can produce this spectrum of morphologic changes R esolving I nfectious C olitis Because most patients not present for endoscopy until several weeks after the onset of symptoms, pathologists are less and less frequently exposed to the classic histologic features of AITC as described previously This is important, because the resolving phase of infectious colitis is more challenging to diagnose At this stage, one may find only occasional foci of neutrophilic cryptitis (focal active colitis) and a patchy increase in lamina propria inflammation, which may, in fact, contain abundant plasma cells and increased intraepithelial lymphocytes (Figure 16-10) Because these features are also seen in Crohn disease and in lymphocytic colitis, it is important to be aware of the patient’s symptoms (particularly acute versus chronic onset) and, ideally, the culture results, because the exact diagnosis may be difficult to resolve on histologic grounds alone ■■ AEROMONAS Aeromonas species, initially thought to be nonpathogenic gram-negative bacteria, are increasingly recognized as causes of gastroenteritis in both children and adults Aeromonas hydrophila and A sobria most often cause gastrointestinal disease in humans Infection usually results from exposure to untreated water but also may result from consuming contaminated foods such as produce, meat, and dairy products C linical F eatures FIGURE 16-9 Focal active colitis in a case of infectious colitis Note focal cryptitis and preservation of crypt architecture Children are most commonly affected, and infections most frequently present in the late spring, summer, and early fall A mild, self-limited diarrheal illness is most common, sometimes accompanied by nausea, vomiting, and cramping abdominal pain A more severe, dysentery-like illness occurs in 15% to 25% of patients, featuring bloody or mucoid diarrhea and fecal leukocytes This variant is most likely to mimic chronic idiopathic inflammatory bowel disease endoscopically A few patients experience a subacute, chronic diarrhea lasting months to years, and the chronic nature of the symptoms may mimic chronic idiopathic inflammatory bowel disease clinically 306 PATHOLOGY OF INFECTIOUS DISEASES FIGURE 16-10 Resolving infectious colitis may show increased plasma cells in the lamina propria, increased intraepithelial lymphocytes, and only rare intraepithelial neutrophils These changes can mimic lymphocytic colitis or chronic idiopathic inflammatory bowel disease AEROMONAS—FACT SHEET Definition ■ Gram-negative bacterial infection usually resulting from exposure to contaminated water; increasingly recognized as cause of infectious enterocolitis Location ■ Colon, often segmental distribution Clinical Features ■ Diarrhea (can be mucoid or bloody); nausea, vomiting, cramping pain Treatment ■ Most cases resolve spontaneously; susceptible to many antibiotics if needed Microscopic Findings The histologic features are usually those of acute selflimited colitis (discussed previously) (Figure 16-11) Ulceration and focal architectural distortion may be seen in some cases (Figure 16-12) A ncillary S tudies Stool cultures are critical to diagnosis AEROMONAS—PATHOLOGIC FEATURES Gross Findings ■ Edema, friability, erosions, exudates, and loss of vascular pattern ■ Often segmental ■ Pancolitis mimicking ulcerative colitis rarely described P athologic F eatures Gross Findings Endoscopically, signs of colitis may be seen, including edema, friability, erosions, exudates, and loss of vascular pattern; the features are often segmental and may mimic ischemic colitis or Crohn disease A pancolitis mimicking ulcerative colitis has also been described Microscopic Findings ■ Usually those of acute self-limited colitis ■ Ulceration and focal architectural distortion may be seen Differential Diagnosis ■ Other enteric infections ■ Crohn disease (gross and microscopic) ■ Ischemic colitis (particularly grossly) ■ Ulcerative colitis (grossly, if pancolitis present) 675 CHAPTER 29 Artifacts and Pitfalls in Infectious Disease Pathology A B FIGURE 29-30 Intracytoplasmic inclusions of CMV on Pap stain (A, 1000 × magnification) Note the granular appearance of these inclusions in this infected cell A characteristic “owl’s eye” inclusion is also present Intracytoplasmic inclusions stain with GMS (B, right panel) and PAS, and thus mimic intracellular yeasts Correlation with H&E in this case (B, left panel) demonstrated characteristic intranuclear inclusions (600 × magnification) VIRAL MIMICS—FACT SHEET A variety of nonviral states may result in the formation of cytoplasmic and nuclear inclusions or multinuclear cells that resemble the viral cytoplasmic effect; morphologic features and staining characteristics allow for their identification ■ In Pap smears, vacuoles resembling koilocytes can be seen in reactive superficial squamous cells, navicular cells, and immature metaplastic cells ■ Melamed-Wolinska bodies or “eosinophilic inclusions” are nonspecific cytoplasmic globules in urothelial cells associated with reactive and degenerated states; they are commonly seen in urine cytology specimens ■ Heavy metal toxicity may cause distinctive intranuclear inclusions in renal tubular cells ■ Malakoplakia is associated with defective bacterial phagocytosis within macrophages and the production of intracytoplasmic Michaelis-Gutmann bodies ■ 676 PATHOLOGY OF INFECTIOUS DISEASES VIRAL MIMICS—PATHOLOGIC FEATURES Unlike true koilocytes, koilocyte mimics such as reactive squamous cells, navicular cells, and cells of squamous metaplasia have less welldefined vacuoles and little to no nuclear atypica ■ Melamed-Wolinska bodies are red to blue, variably sized, cytoplasmic inclusions seen in degenerating urothelial cells; these cells lack characteristics of viral infection such as nuclear inclusions ■ Intranuclear inclusions of lead and other heavy metals manifest in renal tubular cells as distinctive nuclear inclusions with a peripheral rim of condensed chromatin; unlike viral nuclear inclusions, they are relatively small, uniform in size, and acid fast ■ Michaelis-Gutmann bodies are intracytoplasmic targetoid basophilic inclusions that mimic the nuclear inclusions of CMV; their cytoplasmic location and positivity with Von Kossa allow them to be differentiated from viral inclusions ■ A B FIGURE 29-31 Cysts of the free-living amebae, Acantha moeba spp and Balamuthia mandrillaris, may stain with PAS (A, 200 × magnification) and GMS (B, 1000 × magnification) and be mistaken for large yeasts However, the outer cyst wall (exocyst) of free-living amebae is typically round to wrinkled, whereas the internal cyst wall (endocyst) is round, hexagonal, stellate, or polygonal, thus allowing differentiation from similarly sized yeasts 677 CHAPTER 29 Artifacts and Pitfalls in Infectious Disease Pathology A B C D FIGURE 29-32 Koilocytes and koilocyte mimics True koilocytes demonstrate transparent perinuclear halos with crisp demarcation from the outer cytoplasm and enlarged, atypical, hyperchromatic nuclei (A) In comparison, reactive squamous cells (B), navicular cells (C), and cells of squamous metaplasia (D) have less well-defined vacuoles and no nuclear atypica (Pap stain, 600 × magnification) ■■ PARASITES MIMICS Pigment Granules Whereas pigment granules most commonly mimic bacteria and fungi, formalin pigment is an important mimic of the hemozoin produced by malaria parasites Both formalin and hemozoin pigments may be found throughout the body, but malaria pigment is found specifically within erythrocytes in peripheral capillaries and inside macrophages (Figure 29-37), whereas formalin pigment appears as a precipitant, often in a different plane of section, and is not associated with a histiocytic response (see Figure 29-5) Given the potentially life-threatening nature of malaria, it is essential to make a timely and accurate identification of hemozoin pigment A steroid H yalosis B odies Asteroid hyalosis is a degenerative process of the eye, manifesting as opaque calcified bodies (asteroid hyalosis bodies, A-H bodies) in the vitreous humor This is a rare condition, found unilaterally in 75% of cases, and is most common in the elderly It is not usually clinically significant, but rarely dense A-H bodies may interfere with vision and require surgical removal Larger A-H bodies may be seen on slit-lamp examination, whereas smaller A-H bodies may be seen microscopically in vitreous aspiration specimens and be mistaken for parasites or fungi On Pap stain, they appear as blue-purple, amorphous, round to oval-shaped bodies with an inner radial granular appearance that is enhanced using polarized light (Figure 29-38) They are composed of complex lipids, calcium, and phosphorous and stain positively with oil red O and Alcian blue stains 678 PATHOLOGY OF INFECTIOUS DISEASES A B FIGURE 29-33 Reactive endocervical cells may have enlarged, hyperchromatic nuclei, as seen in this cervical biopsy with an inflammatory background (A, H&E stain, 200 × magnification) Focal multinucleation may occur (B, H&E stain, 400 × magnification), but the nuclei lack the characteristic viral changes seen in HSV and VZV infection such as marginated and “ground glass” chromatin L iesegang R ings Liesegang rings, discussed earlier in the fungal mimics section, are rare and found primarily in renal cysts, where they may be confused with fungi or eggs of the giant kidney worm, Dioctophyma renale This worm infects a variety of fish and frog-eating mammals but is only rarely found in humans The eggs of D renale are constant in size and measure approximately 70 μm × 45 μm, whereas Liesegang rings vary in size from μm to 1000 μm (see Figure 29-20) U ric A cid C rystals Uric acid crystals are commonly found in urine, particularly in acidic urine that has been allowed to stand without fixative prior to examination They are clear to 679 CHAPTER 29 Artifacts and Pitfalls in Infectious Disease Pathology FIGURE 29-34 Melamed-Wolinska bodies are variably sized, red-pink or blue cytoplasmic inclusions in reactive or degenerating urothelial cells in urine cytology specimens Pap stain, 600 × magnification FIGURE 29-35 Intranuclear inclusions within renal tubular cells associated with lead toxicity Pap stain, 600 × magnification yellow-brown in unstained specimens and may appear colorless to light green in Pap-stained specimens Their shape can vary tremendously, with diamond-, rhombic-, needle-, lemon-, and barrel-shaped forms being seen Of particular interest is the lemon- or diamond-shaped crystals, which bear a striking resemblance to Schistosoma hematobium eggs Uric acid crystals can be easily differentiated from parasite eggs, however, by their lack of internal nuclei on Pap stain, smaller size (generally 30 to 100 μm in length), variation in size and shape, refractile and occasionally fractured appearance, and birefringence with polarized light Uric acid crystals also commonly have points on both ends, whereas S hematobium eggs have a single terminal spine (Figure 29-39) The eggs of Schistosoma are not birefringent Uric acid crystals are not considered pathologic unless seen in freshly voided 680 PATHOLOGY OF INFECTIOUS DISEASES A B C FIGURE 29-36 Michaelis-Gutmann bodies of malakoplakia are variably sized targetoid-appearing intracytoplasmic vacuoles (A, H&E stain, 400 × magnification), which stain positively for phosphate and carbonate (B, Von Kossa stain, 200 × magnification) Immunohistochemistry for CD68 demonstrates the macrophage lineage of the cells containing the cytoplasmic bodies (C, 400 × magnification) 681 CHAPTER 29 Artifacts and Pitfalls in Infectious Disease Pathology A B FIGURE 29-37 At low magnification (A, 100 × magnification), the abundant brown-black pigment in this section of spleen may be mistaken for formalin pigment However, higher magnification (B, 1000 × magnification) reveals the intraerythrocytic and intramonocytic location of the pigment, consistent with malaria pigment urine, in which case they may be associated with gout, leukemia, or chemotherapy treatment for malignancy F oreign B odies As discussed earlier in the section on fungal mimics, a number of foreign bodies may be introduced into human tissue or the pathology specimen, including splinters, starch, gels, pollen grains, embolic material, food/fecal material, and insects parts The challenge pathologists face when observing these objects in histologic or cytologic preparations is to differentiate them from a variety of infectious entities, including parasites, and to determine their clinical significance for the patient Given the wide variety of foreign bodies that may be seen, only the more common entities are discussed here FIGURE 29-38 A cluster of asteroid hyalosis bodies in a vitreous aspirate (Pap stain, 400 × magnification) from an elderly male suspected of having orbital lymphoma Asteroid hyalosis bodies were noted, and there was no evidence of lymphoma A B C D FIGURE 29-39 Uric acid crystals in urine cytology specimens (A-C, Pap stain, 400 × magnification) compared to a true Schistosoma hematobium egg (D, Pap stain, 400 ×, magnification) Note the fractured appearance of the crystals, size variation, and lack of internal staining nuclei The crystals have points on both ends, or even laterally (C), whereas S hematobium eggs have a well-defined terminal spine (D, Image courtesy of Dr Gladwyn Leiman, University of Vermont.) 683 CHAPTER 29 Artifacts and Pitfalls in Infectious Disease Pathology Fecal/Food Material Fecal material, including bacteria, fungi, vegetable, and animal material, is not uncommonly seen in specimens communicating with the gastrointestinal tract or in the lung (secondary to aspiration) Plant material is usually easily recognized based on its rigid rectangular or square walls, occasional pigment, or circumferential arrangement (Figure 29-40) Although round to oval objects such as seeds may superficially mimic cross sections of roundworms, an understanding of worm anatomy is usually sufficient for differentiating these entities Specifically, roundworms have a distinct outer cuticle, circumferential musculature, and internal structures (e.g., gut, testis, ovaries) When in doubt, consultation with a parasite specialist such as the Centers for Disease Control and Prevention DPDx group (www.dpd.cdc.gov/dpdx/HTML/Contactus.htm) is recommended Splinters Plant cells may also be present in tissues in the form of splinters Again, the presence of rigid square or rectangular cell walls is helpful in making the identification (Figure 29-41) Of note, splinters typically provoke an inflammatory reaction and may introduce fungi or bacteria into the tissue Embolic Material A variety of exogenous and endogenous materials may embolize and be seen within small and medium-sized blood vessels (Figure 29-42) Identification of the surrounding blood vessel wall and careful correlation with the clinical history are important for interpreting the morphologic findings and differentiating thrombosed vessels containing foreign material from parasites An elastin stain may be useful for identifying the outline of the blood vessel wall A B C D FIGURE 29-40 Fecal material Vegetable material is relatively easy to recognize when rigid plant cell walls are readily apparent, such as this material from an appendiceal lumen (A, H&E stain, 100 × magnification) On higher magnification, rigid-walled square cells and a pigmented outer coat are identified (B, H&E stain, 400 × magnification) In another case, the food material is less readily identified (C, H&E stain, 400 × magnification) but lacks clear roundworm features such as the lateral alae and internal uterus as seen in this cross section of pinworm (D, H&E stain, 400 × magnification) 684 PATHOLOGY OF INFECTIOUS DISEASES A B FIGURE 29-41 This splinter was associated with an acute surrounding inflammatory response (A, H&E stain, 100 × magnification) and had introduced a dematiaceous fungus into the skin Brown pigmented hyphae can be seen originating from the splinter (arrowhead) and invading surrounding tissue (B, H&E stain, 400 × magnification) Note the readily identifiable rigid plant cells in the center of the splinter H ost C ells Macrophages In addition to confounding staining patterns of WBCs using PAS and GMS as described previously, activated macrophages may also have bubbly cytoplasm and be mistaken for amebic trophozoites (Figure 29-43) However, the nu- cleus of macrophage is dissimilar from those of trophozoites due to E histolytica and the free-living amebae (see Figure 29-27; see also Chapter 28 on protozoal infections) Ciliocytophthoria Ciliocytophthoria is the phenomenon in which the proximal portion of ciliated columnar epithelial cells has 685 CHAPTER 29 Artifacts and Pitfalls in Infectious Disease Pathology A B FIGURE 29-42 Embolic material from an aortic graft is seen within subcutaneous blood vessels on H&E at low magnification (A, arrowhead, 40 × magnification) At higher magnification (B, 400 × magnification), the foreign nature of the basophilic graft material and surrounding blood vessel wall can be appreciated detached (also known as detached ciliary tufts) and is found free-floating in respiratory specimens and body fluids Detached ciliary tufts measure 10 to 20 μm in diameter and are not uncommonly mistaken for ciliated parasites In wet preps of unfixed specimens, the cilia are often still moving in a synchronized beating motion and easily identified It is important to recognize that the only ciliated parasite of humans is Balantidium coli, a large protozoa with ciliated trophozoites measuring up to 200 μm Balantidium coli has a characteristic kidney bean–shaped nucleus, whereas no nuclear-like structures are seen in detached ciliary tufts Finally, detached ciliary tufts often demonstrate a terminal bar where the cilia were originally attached to the underlying cell, whereas B coli trophozoites are circumferentially covered by cilia (Figure 29-44) 686 PATHOLOGY OF INFECTIOUS DISEASES A B FIGURE 29-43 Activated macrophages in a case of bacterial pneumonia (A) Note the enlarged and somewhat bubbly cytoplasm and large nuclei with a clear outer nuclear membrane and small discreet nucleolus Some cells are multinucleated In comparison, a trophozoite of Acanthamoeba spp causing amebic pneumonia has foamy cytoplasm and a distinct small nucleus with large central karyosome (B, arrow) (H&E stain, 400 × magnification) 687 CHAPTER 29 Artifacts and Pitfalls in Infectious Disease Pathology A B FIGURE 29-44 Ciliocytophthoria demonstrating two eosinophilic detached ciliary tufts (A, center, Pap stain, 600 × magnification) The ciliary tufts consist of the round two-dimensional terminal bar from which the cilia originate The only ciliated human parasite Balantidium coli is much larger and has a distinctive macronucleus (B, H&E stain, 1000 × magnification) 688 PATHOLOGY OF INFECTIOUS DISEASES PARASITE MIMICS—FACT SHEET A variety of endogenous and exogenous materials and host structures can resemble parasites; the size, shape, and staining properties of the objects, as well as careful correlation with the clinical history, are usually sufficient for accurately identifying parasite mimics ■ A second opinion from an expert may be essential ■ Asteroid hyalosis bodies are opaque calcified bodies within vitreous fluid ■ Liesegang rings are uncommonly observed laminated structures associated with benign cysts and inflammatory tissue in a variety of organs; in the kidney, they must be differentiated from the eggs of the giant kidney worm, Dioctophyma renale ■ Urate crystals are commonly seen in acidic urine that has been allowed to stand without fixative prior to examination ■ A wide variety of foreign bodies including fecal material, splinters, starch particles, pollen grains, and insect parts may be introduced into human tissue or pathology specimens; careful correlation with the clinical presentation, associated host response, and location in the tissue are essential for distinguishing these objects from infectious agents such as parasites ■ Activated or foamy macrophages may mimic amebic trophozoites, whereas detached ciliary tufts of ciliocytophthoria may mimic ciliated protozoa ■ PARASITE MIMICS—PATHOLOGIC FEATURES Formalin pigment may mimic the hemozoin pigment of malaria parasites but is differentiated by its clumped appearance and extracellular location ■ Asteroid hyalosis bodies are blue-purple, amorphous, round to oval-shaped bodies with an inner radial granular appearance that is enhanced using polarized light; they are composed of complex lipids, calcium, and phosphorous and stain positively with oil red O and Alcian blue stains ■ Liesegang rings are round to oval, vary in diameter from 5 μm to 1000 μm, and consist of a dense central core and outer rings with faint radial striations; they can be differentiated from the eggs of the giant kidney worm, Dioctophyma renale, by their smaller size and correlation with clinical history ■ Uric acid crystals are colorless to light green in Pap-stained specimens and may resemble Schistosoma hematobium eggs due to their occasional diamond shape; they can be differentiated from S hematobium eggs by their lack of internal nuclei on Pap stain, smaller size, variation in size and shape, refractile and occasionally fractured appearance, birefringence with polarized light, and presence of points on both ends ■ Plant material is usually easily recognized based on its rigid rectangular or square walls, occasional pigment, or circumferential arrangement; features of worms such as a thick outer cuticle, muscular layer, and internal digestive and reproductive structures are lacking ■ Embolic material may be seen within small and medium-sized blood vessels; recognition of the surrounding blood vessel wall and careful correlation with the clinical history are important for interpreting the morphologic findings ■ Activated macrophages have bubbly cytoplasm like amebic trophozoites but have a larger nucleus and different chromatin pattern than the trophozoites of E histolytica and the free-living amebae ■ Detached ciliary tufts measure 10 to 20 μm in diameter and not have a nucleus, whereas trophozoites of the only ciliated parasite of humans, Balantidium coli, measure up to 200 μm and have a kidney bean–shaped macronucleus ■ Suggested Readings available on Expert Consult ... 303 304 PATHOLOGY OF INFECTIOUS DISEASES TABLE 16 -2 Enteric bacterial infectious mimics of chronic idiopathic inflammatory bowel disease and ischemic colitis Mimics of Crohn Disease Mimics of Ulcerative... infiltrate at the edges of ulcers Small vessel vasculitis and microthrombi may be seen, as well as mucosal hemorrhage and crypt withering Pneumatosis may be 322 PATHOLOGY OF INFECTIOUS DISEASES FIGURE 16-30... recommend segmental resection of the involved bowel Surgery may be required to prevent or treat perforation in severe cases 324 A PATHOLOGY OF INFECTIOUS DISEASES B FIGURE 16- 32 A, Neutropenic enterocolitis