git.pptxchhvjbjvuvuhjvj j ibubibjuvubibǰ

Hchcjvfhcjchdufjchcufucj

1. AIDS RELATED IMFLAMMATORY DISEASES OF GIT Moderator Dr.Vandana Mam Presented by Dr.Saritha Rani

2. In 2004, the World Health Organization (WHO) identified HIV/AIDS as the world’s most urgent public health challenge, as AIDS represents the greatest lethal epidemic in recent history. The gastrointestinal (GI) tract is a major site of disease in HIV infection: almost half of all HIV- infected patients present with GI symptoms, and almost all patients develop GI complications.

3. GI symptoms, such as anorexia, weight loss, dysphagia, odynophagia, abdominal pain, and diarrhea, are common and usually non-specific in this population. Endoscopy is the diagnostic test of choice for most HIV-associated GI diseases, as endoscopic and histopathologic evaluation can render diagnoses in patients with non-specific symptoms. Pathologic evaluation of endoscopic biopsy specimens includes light and electron microscopy, special stains, immunohistochemical techniques, fluorescent in situ hybridization (FISH), and polymerase chain reaction (PCR).

4. Light microscopy, with hematoxylin and eosin (H & E) staining, is often sufficient to suggest or confirm a diagnosis. Special stains can be used to highlight specific disease characteristics: periodic acid-Schiff with diastase (PASD) stains highlight acid mucopolysaccharides, glycogen, and pseudohyphae in candidiasis; Grocott’s methenamine silver (GMS) stains reveal fungal elements such as Candida, Histoplasmosis, and Cryptococcus. Acid- fast bacilli (AFB) stains demonstrate mycobacterial bacilli, as in mycobacterium avium- intarcellulare (MAI) infection; Warthin-Starry stains are used for spirochetes; and Brown-Brenn stains aid in the diagnosis of microsporidia

5. CANDIDA ESOPHAGITIS Candida esophagitis can complicate the ulcers of herpes or CMV esophagitis or appear in the absence of viral infection, usually in immunosuppressed individuals, but it may be seen in immuno competent individuals as well. At endoscopy, it typically appears as white plaques that are often easily scraped away. Microscopically Pseudohyphae can be seen in a background of active esophagitis in some cases, special stains (periodic acid–Schiff [PAS], silver stain) may be of use.

6. ESOPHAGITIS DISSECANS SUPERFICIALIS Esophagitis dissecans superficialis (“sloughing esophagitis”) is an endoscopically defined disease characterized by detachment of large fragments of squamous esophageal mucosa. It affects mainly adults, with a female predominance.The etiology is unknown, and the usual evolution is towards total resolution. Microscopically, there is “sloughing” and “flaking” of the superficial squamous epithelium, with occasional bullous separation of the layers, para keratosis, and nonspecific inflammation (Fig. 13.11).

7. Herpes Esophagitis Esophagitis due to herpes simplex virus is usually seen as an opportunistic infection in immunosuppressed patients, but it also can occur in otherwise healthy children and adults Grossly, the mucosa exhibits small vesicles that evolve into discrete shallow ulcers; in severe cases, these coalescence into extensive zones of mucosa. The ulcer bed is histologically undistinguished, consisting of necrotic debris and neutrophil-rich inflammatory exudate. The diagnostic herpetic inclusions are located in discohesive or multinucleated squamous cells at the margins of the ulcers (Fig. 31.8A).

8. The characteristic inclusions include dense, eosinophilic, intranuclear (Cowdry type A) bodies, which are separated from a thickened nuclear membrane by a clear halo, and homogeneous ground-glass inclusions that fill the nuclei. Herpetic ulcers may be secondarily infected by fungi or bacteria. In healthy hosts, herpes simplex esophagitis is usually self-limited, but in patients with an underlying predisposing condition, the result may be esophageal perforation or disseminated infection.

9. Cytomegalovirus Esophagitis CMV can infect the esophagus of immunocompromised patients and only rarely normal individuals, producing ulcers similar to those of herpes simplex esophagitis . The ulcer bed is the diagnostic focus: enlarged mesenchymal cells of the granulation tissue contain the heralded CMV inclusions conspicuous intranuclear bodies surrounded by a clear halo together with, in many infected cells, coarse intracytoplasmic granules (Fig. 31.9).

10. In patients under antiviral therapy, however, the inclusions may be less distinctive and the appearances mistaken for enlarged and reactive but noninfected cells. The presence of macrophage aggregates within the granulation tissue, particularly in a perivascular distribution, may be a diagnostic clue to CMV esophagitis . Immunostains are valuable in establishing the diagnosis when definitive inclusions are not seen.

11. HIV-ASSOCIATED DIARRHEA HIV-Associated Diarrhea is the most common GI symptom in HIV infected patients, affecting up to 90% of patients, and increases in frequency and severity as immune function deteriorates. The most common HIV-associated diarrheal pathogens include Cryptosporidium , non tubercular mycobacteria, microsporidia, bacteria ( Salmonella, Shigella, Campylobacter, and E. coli ) .

12. Despite the controversial role of bidirectional endoscopy in the evaluation of HIV-associated diarrhea, the following diagnostic algorithm has been suggested: in patients with diarrhea, a CD4 count less than 100/mm 3 and inconclusive routine stool studies. T he best overall diagnostic test is colonoscopy with terminal ileal intubation and biopsy; in patients with CD4 counts of 100–200/mm 3 , flexible sigmoidoscopy and biopsy are sufficient, because CMV infection is less likely to occur at higher CD4 counts .

13. If diagnostic doubt remains, duodenal biopsies may be useful, especially in patients with lower CD4 counts . The role of routine stool studies for ova, parasites, and so before endoscopy and biopsy—cannot be over emphasized.

14.   HIV-Associated Small Bowel Pathology (Tables 1 and 2 ; Figures 1 and 2 ). Intestinal biopsies and aspirates from HIV-infected patients may reveal HIV enteropathy, CMV, MAI, protozoa ( Cryptosporidium , Isospora, microsporidia, Giardia ), helminths ( Strongyloides stercoralis ), and fungi ( Histoplasma capsulatum )—all of which may cause malabsorption and/or diarrhea. The organisms most commonly found on duodenal biopsies include CMV, Cryptosporidium , microsporidia, and Giardia [ 3 ].

15. Small bowel protozoal infections cause irregular, fused, widely-spaced, shortened villi, resulting in an erythematous, granular appearance on endoscopy ( Figure 1 ) [ 5 ]. Cryptosporidia are small (2–5 µ m), round, basophilic organisms, which appear on the luminal borders of enterocytes, submucosal glands, and ducts on light microscopy ( Figure 2 ); surrounding villi are variably atrophic, with infrequent crypt abscesses and neutrophils in the lamina propria. Both Cryptosporidia and microsporidia are often missed on routine biopsies, as their subtle appearance is better appreciated with electron microscopy.

16. If microsporidia spores are not identified in stool samples or duodenal aspirates, Brown-Brenn stains may aid in visualization. Moreover, microsporidia can be reliably diagnosed using a modified trichrome stain, PCR analysis of stool specimens, or FISH. Enteric isosporiasis, secondary to opportunistic Isospora belli infection, is more common in HIV-infected patients in developing countries than in the United States or in Europe. Isosporiasis localizes to the small bowel, but can spread to the colon and regional lymph nodes. Diagnosis is facilitated by identification of Strongyloides stercoralis is a parasitic nematode with a predilection for the small intestine [ 2 ].

17. Strogyloides stercoralis Strongyloides stercoralis is a parasitic nematode with a predilection for the small intestine [ 2 ]. Intestinal lesions can be divided into three morphologic categories: ( i ) catarrhal enteritis, in which the small bowel appears congested with abundant mucus secretion, petechial hemorrhages, and submucosal mononuclear inflammation; (ii) edematous enteritis, in which the bowel wall is thickened, the mucosal folds are flattened, and the submucosa shows edema and inflammation; (iii) ulcerative enteritis, in which the bowel wall is rig id, fibrotic, and ulcerated, with abundant neu- trophilic infiltrates.

18. HIV Enteropathy HIV enteropathy often causes severe malabsorption, lac tose intolerance, vitamin B12 and D-xylose malabsorption, and increased intestinal permeability with protein loss [ 3 ]. While the pathophysiology of HIV enteropathy-induced diarrhea remains unclear, there are currently two hypotheti cal mechanisms: ( i ) mucosal HIV infection affects intestinal permeability by disrupting tight junctions, epithelial apoptotic activity, or both [ 16 ]; (ii) coupled with a coreceptor, HIV protein gp120 causes calcium-mediated microtubule loss and cellular instability results [ 17 ]. Endoscopically, HIV enteropathy may manifest as “frosted” mucosa [ 3 ]; histopathologic changes include villous blunting and widening, vacuolated enterocytes, and increased inflammatory cells in the lamina propria. Initiation of highly active antiretroviral therapy (HAART) leads to resolution of both clinical symptoms and ultrastructural tissue changes.

19. Other Infections Associated with HIV Rare examples of fungal esophagitis caused by Aspergillus and the Phycomycetes are reported. In addition, histoplasmosis, blastomycosis, and cryptococcosis may involve the esophagus, usually in association with either disseminated or mediastinal disease . Unusual examples of varicella-zoster virus esophageal infections have also been reported.Bacterial colonization of esophageal ulcers is a frequent observation but, in severely immunocompromised patients, bacteria can also become a primary opportunistic pathogen. Implicated bacteria include a range of gram-positive and gram-negative organisms, with a mixed population (chiefly representing oropharyngeal flora) commonly noted.

20. Histologically, bacterial esophagitis is characterized by clusters of bacteria invading the esophageal wall and involving blood vessels with associated necrosis. Other unusual esophageal infections include bacillary angiomatosis, tuberculosis, actinomycosis, syphilis, leishmaniasis, Whipple ’s disease and Chagas disease. Idiopathic esophageal ulcers are sometimes found in patients infected with HIV. Although HIV has been identified in these ulcers by IHC and electron microscopic studies, its presence probably does not reflect a pathogenic role, and other as yet unidentified, agents may instead be responsible. The ulcers may heal with empiric therapy using corticosteroids.

21. GASTRITIS IN IMMUNOSUPPRESSED PATIENTS Immunosuppression may occur in patients with the acquired immune deficiency syndrome (AIDS), in bone marrow and solid organ transplant recipients, in patients receiving anticancer chemotherapy, or in patients with inherited immunologic defects infection is one of the more common problems in immunosuppression. The disease is more frequent and more severe in the small bowel and colon but can affect the stomach. In the early stages, the endoscopic appearances may be normal, but on biopsy, typical eosinophilic intranuclear inclusions (Fig. 32.22) may be found, which may or may not be accompanied by smaller, purple-staining, granular cytoplasmic inclusions and a patchy, nonspecific infiltrate in the lamina propria.

22. Initially, the inclusions are present in epithelial cells of the lower portion of the foveolae or in the upper part of the glands. In the more advanced disease, ulceration occurs, and the inclusions become more frequent in mesenchymal cells, usually endothelium. Severe CMV gastritis is manifested by necrosis of epithelium with ulceration , leading to severe hemorrhage or even perforation. Mucosal thickening and polyps may also be encountered. In children with CMV infection, the hypertrophic mucosa may be similar to Ménétrier disease .

23. I NTERPRETATION OF ENDOSCOPIC BIOPSY SPECIMENS FROM IMMUNOSUPPRESSED PATIENTS, INCLUDING PATIENTS WITH HUMAN IMMUNODEFICIENCY VIRUS AND ACQUIRED IMMUNODEFICIENCY SYNDROME Endoscopy and histologic examination play a vital role in the diagnosis and management of patients with immunodeficiency . These patients are at increased risk for opportunistic infections as well as neoplasia, and the lesions can often be subtle. In the last two decades, profound changes have occurred in the medical management of human immunodeficiency virus (HIV) and AIDS with highly active antiretroviral therapy (HAART). This therapy has markedly reduced the incidence of opportunistic infection and is invariably the first-line approach not only for HIV and AIDS but also for the complicating infections.

24. However, the interpretation of intestinal biopsy specimens from patients with untreated HIV and AIDS remains one of the premier challenges in surgical pathology. In addition to infection with microbiologic pathogens, these patients can develop so-called “HIV enterocolopathy” characterized by villous blunting, crypt hyperplasia, apoptosis, and mild intraepithelial lymphocytosis. These findings have been attributed to the effect of HIV on enterocytes, although a variety of viruses have also been detected in the stool of affected patients .

25. COMMON INFECTIOUS AGENTS Bacterial Infection Immunocompromised patients can become infected with the same bacterial pathogens that affect other patients. These include C. difficile , E. coli, and Yersinia, Salmonella, and Shigella species, among others. Diagnosis can be made by identifying the organism in stool culture. When patients undergo biopsy, the specimens often contain the spectrum of changes associated with infectious colitis or acute self-limited colitis. In addition to common pathogens, immunocompromised patients can be infected with a variety of unusual pathogens.

26. Intestinal Spirochetosis Intestinal spirochetosis, caused by Brachyspira aalborgi or Brachyspira pilosicoli , can be seen in patients with HIV or AIDS, as well as in children and in patients with other disorders who do not have HIV infection. Infection is often asymptomatic but children and immunocompromised patients (including those with HIV/AIDS) can present with diarrhea and abdominal pain . The endoscopic appearance is usually unremarkable, and the microscopic appearance is very subtle, with a thickened and “fuzzy” appearance to colonic mucosa on the luminal surface, which is caused by the spirochete organisms embedding themselves into the luminal border of the absorptive cells (Fig. 33.25). They do not attach to goblet cells. Identification of intestinal spirochetosis can be enhanced by the use of the Warthin-Starry stain or by electron microscopy. An immunostain for Treponema species will also highlight the organisms.

27. Mycobacterium Tuberculosis and Avium Complex Mycobacterium tuberculosis (TB) and avium complex (MAC) are well documented pathogens, particularly in HIV-affected areas in Africa . M. tuberculosis can often be identified in the GI tract in patients with active pulmonary disease.Gastrointestinal tuberculosis most often affects the ileocecum but can affect any location of the GI tract. Endoscopically, infected areas have extensive ulceration with subsequent stricture formation . Histologically, these areas have well-formed, caseating granulomas in immunocompetent patients, and neutrophil-rich histiocytic inflammation in those who are immunocompromised .

28. Distinguishing TB infection from Crohn disease can be challenging. Helpful clues suggesting TB include large granulomas with caseous necrosis, abundant histiocyte palisading, and lack of chronic enteritis in surrounding areas. GI tract involvement by MAC is usually part of disseminated infection and can affect any portion of the GI tract. Histologically, there is infiltration of the lamina propria by foamy macrophages that are PASpositive; as such, the histology can closely mimic Whipple disease (Fig. 33.26A) (126,307). However, MAC is typically patchy and lacks the large lipid vacuoles of Whipple’s disease, and the organisms are acid-fast positive (Fig. 33.26B).

29. The infiltrative macrophages may be subtle, and some recommend that an acid-fast stain be done on all mucosal biopsy specimens from patients with HIV or AIDS. HIV-associated infection with Chlamydia trachomatis and Neisseria gonorrhoeae is also well documented and is most commonly associated with proctitis in MSM (303). Infection with syphilis ( Treponema pallidum ) and lymphogranuloma venerum is also common in the distal colon and rectum and can strongly mimic IBD with a robust lymphoplasmacytic infiltrate, architectural changes, and active inflammation.

30. Diagnosis of syphilis often relies on serum testing or special studies performed on rectal tissue, because silver and immunohistochemical staining are not sensitive (308). Diarrheagenic bacterial enterocolitis has been described in patients with HIV or AIDS (309). Colonic biopsy specimens demonstrate surface epithelial inflammation and degeneration associated with Gram negative bacteria adherent to the surface of enterocytes (Fig. 33.27). The histology resembles that seen in EPEC infection (310).

31. Parasitic Infestations Gastrointestinal parasitic infections are common in immunocompromised patients. Before HAART therapy was developed, Cryptosporidium parvum was the most common parasitic infection, typically affecting the proximal small intestine, although involvement of the colorectum was frequently present . In immunocompromised patients, it causes severe, explosive, watery diarrhea that is resistant to most forms of therapy . On endoscopy, the findings are often minimal or nonspecific .

32. Histologically, there is variable villous abnormality, crypt hyperplasia, and a mixed infiltrate with numerous eosinophils . The diagnosis is readily made with a stool sample or PCR on infected specimens (133) or by identifying the organism on histology, where 2 to 5 μm basophilic spheres can be seen protruding below the apical membrane of the epithelium. These stain with acid-fast, Giemsa, Gram, and Warthin-Starry stains and can also be highlighted by immunofluorescence (Fig. 33.28 ) .

33. Microsporidia infections are caused by Enterocytozoon bieneusi and Encephalitozoon intestinalis (formerly known as Septata intestinalis ) (303). They have been recognized in up to 50% of HIV or AIDS patients with chronic unexplained diarrhea (133,309,311,312). The parasites infect the small intestine and can easily be missed on routine histologic sections, because they are small and intracellular (Fig. 33.30). Mature spores measuring 1.5 μm are an inconsistent finding; these stain Gram-positive and can be seen as a cluster of small dots in the apical cytoplasm of the enterocyte (309,313).

34. The nucleated sporont is a larger (3-5 μm ), rounded, basophilic structure often surrounded by a halo and is found in surface enterocytes near the villous tips or in degenerating cells. This form frequently causes a cup-shaped indentation of the enterocyte nucleus that can be an important clue in identification on H&Estained sections. Examination with polarized light can occasionally accentuate the organisms polar filament (303).

35. Giardia lamblia Infection by G. lamblia is common, especially in underdeveloped countries or in areas where the water supply is contaminated by fecal material . It is also the most common protozoal disease in the United States. The first signs of infection usually appear after 6 to 15 days and include explosive, foul-smelling watery diarrhea, nausea, epigastric pain, and weight loss. Endoscopic examination is typically unremarkable, and histologic changes in small intestinal biopsies can be subtle and challenging to identify. Diagnosis can be aided with the use of stool examination, enzyme-linked immunosorbent assays (ELISA), direct immunofluorescent antibody microscopy on stool samples, or PCR .

36. Although pathologists usually encounter Giardia in duodenal biopsy specimens, the organism has been found in the gastric antrum, ileal specimens, and even colonic biopsy specimens. In fact, a recent study showed that in patients whose duodenal biopsies had histologic features suggesting the possibility of Giardia but in which identifiable organisms were absent, they could actually, be found in ileal biopsies . Although most biopsies in patients with giardiasis are essentially unremarkable apart from the presence of the organisms, they can occasionally have mild villous blunting with inflammatory expansion of the lamina propria (Fig. 33.10) .

37. The histologic diagnosis rests on the demonstration of Giardia trophozoites along the surface of epithelial cells in biopsy specimens (Fig. 33.11).Morphologically, the trophozoite has a “pear-shaped” appearance with two prominent nuclei. They often appear as if they are “falling off” the mucosa-like leaves and, for this reason, may be overlooked under the assumption that they are simply mucus from the goblet cells on the villi. Special stains such as Giemsa or trichrome can assist in the diagnosis, although H&E preparations typically sufficient. When trophozoites are identified, the lamina propria should carefully be examined for plasma cells because Giardia is commonly seen in patients with CVID.

38. Strongyloides Stercoralis Strongyloides stercoralis is a nematode endemic to the tropic and subtropic regions and the south eastern United States. Interestingly, immunocompromised patients on chronic steroid therapy and with a history of solid organ transplantation are at a higher risk for infection than those with HIV/AIDS, which does not appear to be a significant risk factor (302). Transmission occurs when filariform larvae, which exist in soil, penetrate exposed skin and migrate to the duodenum and jejunum, where females lay eggs.

39. Patients can be infected for decades with only mild symptoms. Hyper infection occurs in immunocompromised patients, and symptoms include diarrhea, vomiting, intestinal obstruction, and protein losing enteropathy. Endoscopy is nonspecific and histology mixed inflammation with large curved organisms with pointed tails and basophilic ova, within intestinal crypts (302). Identification of larvae or eggs in stool or tissue leads to a diagnosis; one can also use serologic detection of Strongyloides immunoglobulins.

40. Kaposi Sarcoma Kaposi sarcoma remains the most common HIV-associated GI malignancy, and the GI tract is the second most common organ system involved after the skin (321,325). Patients are usually asymptomatic but may present with nausea and abdominal pain. Gastrointestinal hemorrhage can also be a presenting symptom, although this is typically with more advanced disease. Grossly and endoscopically, Kaposi sarcoma appears as red macules or nodules.

41. Histology usually reveals a mildly atypical spindle cell proliferation with poorly formed, slit-like blood vessels and abundant erythrocytes (Fig. 33.31). Immunostaining for HHV-8 can confirm the diagnosis. Kaposi sarcoma can be positive for CD117 and DOG-1, so it is important to rule out other spindle cell tumors of the GI tract such as gastrointestinal stromal tumors (GISTs) (321,326).

42. Epstein-Barr virus–associated smooth muscle tumor Epstein-Barr virus (EBV)–associated smooth muscle tumor is a rare neoplasm that can occur in the setting of HIV/AIDS infection. The GI tract is a common anatomic site, and the lesions present as nodules with central ulceration. Histologically, they appear as classic smooth muscle tumors (leiomyoma or leiomyosarcoma) but with abundant T-cell inflammation (321).

43. EBV infection can be confirmed with in situ hybridization. Treatment relies on reestablishing efficient T-cell immunity such as initiation of HAART in HIV patients or reduction of immunosuppression in patients with organ transplantation. Surgery should be performed whenever tumor masses affect organ function. Chemotherapy and radiotherapy can be used if these other measures do not improve the disease course (327).

44. References 1. Kumar, V.Abbas , A.K.,Aster , J.C., & Perkins, J.A. (2018). Robbins Pathologic basis of disease (Tenth edition.).South asia : Elsevier. 2. Rosai, J., Ackerman,L.V . and Rosai, J (2011) Rosai and Ackerman’s Surgical Pathology 10 th edition, Mosby, New York. 3. Mills & Sternberg’s Teri A. Longacre ; vol 1&2 Diagnostic Surgical Pathology 7 th Edition , New York. 4 .T. A. Knox, D. Spiegelman, S. C. Skinner et al., “Diarrhea and abnormalities of gastrointestinal function in a cohort of men and women with HIV infection,” American Journal of Gastroenterology , vol. 95, no. 12, pp. 3482–3489, 2000.

45. 5. S. Di Lollo and S. Tozzinni , “Pathology,” in Textbook-Atlas of Intestinal Infections in AIDS , D. Dionisio, Ed., pp. 211–231, Springer, Milan, Italia, 2003. 6. J. D. Rich, J. M. Crawford, S. N. Kazanjian, and P. H. Kazanjian, “Discrete gastrointestinal mass lesions caused by cytomegalovirus in patients with AIDS: report of three cases and review,” Clinical nfectious Diseases , vol. 15, no. 4, pp. 609– 614, 1992. 7. F. Clayton and C. H. Clayton, “Gastrointestinal pathology in HIV- infected patients,” Gastroenterology Clinics of North America , vol. 26, no. 2, pp. 191–240, 1997. 8. C. M. Wilcox and D. A. Schwartz, “Endoscopic character- ization of idiopathic esophageal ulceration associated with human immunodeficiency virus infection,” Journal of Clinical Gastroenterology , vol. 16, no. 3, pp. 251–256, 1993.

46. THANK YOU