Pathologic Findings in Disseminated Mycobacterium avium-intracellulare Infection

A Report of 11 Cases

DIANE C. FARHI, M.D., ULYSSES G. MASON III, M.D., AND CHARLES R. HORSBURGH, JR., M.D. Downloaded from https://academic.oup.com/ajcp/article/85/1/67/1909056 by guest on 29 September 2021

The pathology of disseminated Myobacterium avium-intracel­ Departments of Pathology and Medicine, University of lulare (MAI) was studied in 20 specimens from 11 patients. The Colorado Health Sciences Center, and Department of patients ranged from 28 to 65 years and included 8 immunosup- Medicine, National Jewish Hospital and Research pressed and 3 immunocompetent hosts. Specimens of lymph node Center, Denver, Colorado (five), spleen (one), liver (four), bone (three), pulmonary tissue (three), skin (three), and an aortic aneurysm were included. All cultured specimens grew MAI, but only two-thirds of these showed acid-fast bacilli (AFB) on staining. Some tissues (liver, We studied disseminated MAI in a selected population spleen) showed granulomas similar to those seen in tuberculosis. of patients without AIDS in an effort to describe the ex­ Other tissues (skin, bone, bronchus) showed necrotizing acute trapulmonary pathologic findings and to ascertain whether and chronic inflammation with histiocytes but no definite gran­ the unusual pathology of MAI reported in some children ulomas. Lymph nodes showed a variety of nonnecrotizing and and AIDS patients is due to the organism itself or altered necrotizing granulomatous lesions. In skin, bone, and some lymph nodes, MAI infection appears to be histopathologically distin­ host response. All of these patients underwent bone mar­ guishable from tuberculosis. The cases reported here are distinct row biopsies; in light of the importance of the bone mar­ from those reported in some children and patients with the ac­ row biopsy in the diagnosis of granulomatous disease,1017 quired immunodeficiency syndrome who have massive histiocytic these form the subject of a separate report.12 infiltrates with innumerable intracellular AFB. This difference may be due to a specific defect in host response involving T-cell macrophage interaction. (Key words: Mycobacterium avium-in­ Materials and Methods tracellulare; Atypical mycobacteriosis; Granulomatous disease) The records of National Jewish Hospital, Denver, Col­ Am J Clin Pathol 1986; 85: 67-72 orado, were searched for cases of culture-documented, disseminated infection with MAI. Disseminated disease HUMAN INFECTION by Mycobacterium avium-intra­ was defined as present when positive cultures were ob­ cellulare (MAI) has attracted increasing interest, partic­ tained from two or more sites, at least one of which was ularly in immunosuppressed patients and those with the extrapulmonary. acquired immunodeficiency syndrome (AIDS).14'30'39,47'48 Fourteen cases were discovered; in 13 cases biopsies Numerous case reports and small series have been pub- and autopsy tissues were available for review. In two cases, lished,2-9-19-21'25'27,32'33,35'37'40-44'46 as well as larger reviews the only tissue obtained was a bone marrow biopsy. Ma­ of the clinical spectrum of disease.3-"•22'31'34-3645 terial from the remaining 11 cases forms the basis of this The pathology of MAI infection has been the subject report. Three of the cases (cases 1,4, 10) have been re­ of debate, especially with regard to its possible distinction 15 21 44 ported in part elsewhere. ' ' from infection with Mycobacterium tuberculosis. Clari­ Slides were evaluated for granulomatous inflammation, fication of this tissue has been hampered by confusion of acid-fast bacilli (AFB), presence and type of necrosis, giant MAI with other nontuberculous mycobacteria and lack cells, and other features. These were compared with cul­ of data pertaining to extrapulmonary infection. Further­ ture results for MAI. Granulomatous inflammation was more, tissue responses in children and in patients with considered present when a mixed infiltrate of foamy or specific immunodeficiency states may be different and epithelioid histiocytes, lymphocytes, and plasma cells was thus not comparable. seen; definite granuloma formation also was recorded. The tissues consisted of lymph nodes (five) and spleen Received February 21, 1985; received revised manuscript and accepted (one), liver biopsies (four), bone biopsies (three), skin for publication April 4, 1985. biopsies (three), lung and transbronchial biopsies (three), Supported in part by grant CA-15823 from the National Institutes of and an aortic aneurysm. In many cases, multiple samples Health and from the R. J. Reynolds Industries, Inc. Address reprint requests to Dr. Farhi: Institute of Pathology, Case of one tissue were received and grouped as a single entry. Western Reserve University, 2085 Adelbert Road, Cleveland, Ohio 44106. In all, 20 specimens were examined. Specimens were

67 68 FARM, MASON, AND HORSBURGH AJ.C.P. • January 1986 Table 1. Clinical Data in Patients with Disseminated Mycobacterium avium-intracellulare

Underlying Clinically Involved Concomitant Case Age Race Sex Condition Sites Infections Outcome

1 56 W M Hairy cell leukemia, BM, liver None Died of SCC at 7 yr; steroids NED 2 64 W M None Nodes, spleen None A & W; NED 3 45 W M Chronic renal failure Aortic aneurysm, BM None A & W; NED 4 41 W F Chronic BM, liver, lung None DiedofCMLat 1 yr myelogenous leukemia 5 45 O/W F None BM, lung, bones None A & W; NED 6 28 W F Steroids BM, nodes, spleen, Multiple bacteria Died of other infections liver and fungi at 2 yr; NED

7 52 W M Splenectomy, Lung, skin, nodes Cryptococcus Died at 2 yr of Downloaded from https://academic.oup.com/ajcp/article/85/1/67/1909056 by guest on 29 September 2021 steroids, cryptococcus and dysmyelopoiesis MAI 8 41 O M Steroids Lung, bones None A & W; NED 9 65 W M Anthracosilicosis Lung, pericardium None Died at 9 yr of respiratory failure 10 32 w M Previous M. Bones None A & W; NED scrofulaceum infection 11 50 w M Multiple myeloma; BM, liver Multiple fungi Died at 1 month steroids

Abbreviations: W = white; O = oriental; BM = bone marrow; SCC = squamous ceil carcinoma; NED = no evidence of disease (MAI); A & W = alive and well; CML = chronic myelogenous leukemia. stained with the Ziehl-Neelsen stain except when other­ were filled with nuclear debris, neutrophils, and lympho­ wise noted. cytes (Fig 1). In only one instance was a "caseous" ap­ Clinical information was obtained from hospital records pearance recognized, in which was found a homogeneous and direct patient contact. The clinical aspects of the dis­ area of acellular, eosinophilic material without nuclear ease are reported in detail separately.18 debris. The rim of the necrotic areas, although composed largely of histiocytes and lymphocytes, did not show an Results organized, palisading arrangement. Giant cells were pres­ The clinical data are summarized in Table 1. Of the ent in low numbers in only two cases. They contained 11 patients, 8 were male and 3 female. The ages ranged two to four nuclei grouped in the center of the cell, sur­ from 28 to 65 years; nine were white and two Oriental. rounded by vacuolated cytoplasm. A significant popula­ Four had major hematologic disorders (hairy cell leuke­ tion of neutrophils was present, admixed with chronic mia, chronic myelogenous leukemias, dysmyelopoietic inflammatory cells, throughout the involved areas. In one syndrome, multiple myeloma), and five were treated with instance, eosinophils were a prominent part of the in­ steroids (prednisone in each case) for real or suspected flammatory infiltrate. Rare AFB were identified in all illnesses. In three cases, other possibly predisposing factors nodes except those from case 10; in that case, the specimen were present (anthracosilicosis, chronic renal failure, pre­ showed few granulomas and was stained with night blue vious Mycobacterium scrofulaceum infection). In two for AFB. Four of the five sets of nodes were cultured; all cases, there was no apparent underlying contributory grew MAI. cause. Therapy was generally effective in eradicating the disease. Although six patients died, only two had conclu­ Spleen sive evidence of persistent active disease that may have The spleen showed numerous small clusters of epithe­ been a factor in their deaths (cases 4 and 7). lioid histiocytes without necrosis. Giant cells resembling The pathologic findings are summarized in Table 2. those described above were found easily. Neutrophils and When present, organisms were observed within histiocytes plasma cells were not prominent. Lymphoid tissue was at the edge of necrotizing lesions and within nonnecro­ increased. The spleen failed to show AFB but grew MAI. tizing granulomas. Liver Lymph Node Four needle biopsies of the liver were examined; three The five sets of lymph nodes examined each showed of these contributed to the initial diagnosis of dissemi­ definite, well-formed epithelioid granulomas, frequently nated MAI. The three diagnostic biopsies showed multiple with abscess formation; necrosis was present in all but small, nonnecrotizing granulomas randomly distributed one of these specimens. The necrotic areas almost always throughout the hepatic lobules (Fig. 2). The lesions were vol. 85-No. l PATHOLOGY OF DISSEMINATED MAI INFECTION £0, Table 2. Tissue Findings in Patients with Disseminated Mycobacterium avium-intracellulare Infection

Granulomatous Culture Giant Case Tissue Inflammation* AFB for MAI Necrosis Cells Remarks Liver biopsy ++ + + Nuclear debris, PMNs Skin of neck + + ND Foamy histiocytes, PMNs, microabscesses Cervical node ++ + ND + Necrotizing granulomas Axillary node ++ + + + Aortic aneurysm + + + NR Acute and chronic aortitis with granulotous inflammation and abscesses

4 Liver biopsy ++ + - PMNs Downloaded from https://academic.oup.com/ajcp/article/85/1/67/1909056 by guest on 29 September 2021 5 Transbronchial + ND + - Dense infiltrate of biopsy lymphocytes, PMNs, histiocytes, eosinophils Rib biopsy - Dense infiltrate of lymphocytes, PMNs, histiocytes, eosinophils, plus increased PCs, microabscesses 6 Mediastinal and ++ + + + Few Increased PMNs and cervical nodes eosinophils Spleen ++ - + — Mod. Marked epithelioid granulomas Abdominal ++ + + + Few Caseous necrosis nodes 7 Skin biopsy + + + + - Microabscesses, PMNs 8 Femur biopsy + + + - Transbronchial + + - Scanty chronic biopsy " inflammation 9 Lung ++ + + + Rare Many PMNs, nuclear debris 10 Skull + ND NR + - Many PMNs, PCs, foamy histiocytes, epithelioid granulomas Axillary node + _ + _ 11 Liver biopsy ++ - + - PMNs Abbreviations: A = autopsy; ND = not done; NR = not recorded; PMN = polymorphonuclear • "+" indicates a mixed infiltrate of histiocytes, lymphocytes, and plasma cells;"++" indicates neutrophils; PC = plasma cells. well-formed granulomas. composed of histiocytes with lesser numbers of lympho­ histiocytes was not a prominent feature. Intracellular AFB cytes; as in the other specimens, neutrophils were a sigr were present, and the specimen grew MAI. nificant component of the granulomas,, and scanty nuclear debris occasionally was observed. Eosinophils and plasma Bone cells were not prominent. All grew MAI on culture, but Three bone biopsies were reviewed, from rib, femur, only one showed AFB. and skull. Each showed evidence of chronic inflammation and fibrosis; in addition, the skull and rib contained Lung abundant neutrophils and marked numbers of plasma The three examples of pulmonary tissue included two cells and foamy histiocytes (Fig. 3). Microabscesses and transbronchial biopsies and sections of lung taken at au­ eosinophils were present in the rib. Giant cells were absent topsy. The biopsies showed a mixed chronic inflammatory in all cases. Both specimens that were stained for AFB cell infiltrate of lymphocytes and histiocytes without were positive. Both cultured specimens grew MAI. granuloma formation. In case 5, neutrophils and eosin­ ophils were prominent. Giant cells and necrosis were ab­ Skin sent. An AFB stain was done in only one and was negative; The three skin specimens consisted of two biopsies and however, cultures were positive for MAI in both. Lung autopsy tissue. Each showed unremarkable epidermis sections from case 9 showed numerous large and small overlying a massive, deep dermal infiltrate, extending necrotizing granulomas prominently infiltrated with neu­ widely into subcutaneous adipose tissue (Fig. 4). Skin ap­ trophils. Areas of necrosis were filled with nuclear debris pendages were surrounded by inflammation at the margin and neutrophils; giant cells were rare, and palisading of and destroyed at the center of the lesion. Lymphocytes, 70 FARHI, MASON, AND HORSBURGH A.J.C.P. • January 1986 Downloaded from https://academic.oup.com/ajcp/article/85/1/67/1909056 by guest on 29 September 2021

FIG. 1 (upper, left). Lymph node, showing irregular, poorly defined necrotizing lesions (X90). FIG. 2 (upper, right). Liver biopsy, showing a representative small nonnecrotizing granuloma, composed predominantly of lymphocytes and histiocytes (X200). FIG. 3 (lower, left). Bone biopsy, displaying acute and chronic inflammation with new bone formation. Well-formed granulomas and caseous necrosis are absent (X90). FIG. 4 (lower, right). Skin biopsy, showing deep dermal and subcutaneous chronic inflammation, without granulomas or caseous necrosis (X63). Vol. 85 • No. I PATHOLOGY OF DISSEMINATED MAI INFECTION 71 foamy histiocytes, and neutrophils were present, with ir­ Numerous case reports and short series have described regular areas of necrosis and abscess formation. The ne­ aspects of the pathology of MAI infection. Most of these crotic areas contained abundant nuclear debris and intact reports are consistent with the findings reported here. inflammatory cells. Granulomas were not formed, and However, we did not see any cases of massive foamy his­ giant cells were absent. Each of the lesions showed scanty tiocytic proliferation in which the cells are filled with in­ intracellular AFB. Only one specimen was cultured; it numerable AFB. Such cases have been reported almost 7 22 25 27,42 grew MAI. exclusively in children, - ' ' frequently male infants with a history of early and repeated infections, and in Aortic Aneurysm AIDS patients.I3'6'39'47 Such cases appear to have a very Acute and chronic aortitis was present with granulo­ poor granulomatous response with production of massive matous inflammation and abscess formation. Intracellular numbers of intracellular organisms resembling leproma- tous leprosy.39*47 The findings in our cases suggest that

AFB were identified, and the specimen grew MAI. Downloaded from https://academic.oup.com/ajcp/article/85/1/67/1909056 by guest on 29 September 2021 some children and AIDS patients have a different response Discussion to MAI, based on host factors rather than the organism Certain histopathologic differences emerged between itself. organ groups. Liver biopsies and the spleen showed only The nature of the predisposing immunologic defect in nonnecrotizing granulomas, whereas transbronchial disseminated MAI infection has been under investiga­ biopsies, skin, and bone showed a mixed infiltrate of his­ tion.40 Lymphokine production, specifically gamma in­ tiocytes, lymphocytes, and neutrophils with necrosis but terferon, appears altered in AIDS patients29 and may have no granuloma formation. Lymph nodes spanned both an effect on macrophage response. Of interest in this re­ classes, exhibiting a range of findings from small non­ gard is the occurrence of a case of disseminated MAI with necrotizing granulomas to irregular areas of acute and massive histiocytic infiltration in association with intes­ chronic inflammation with abscess formation rimmed by tinal malakoplakia, a disorder of altered macrophage histiocytes. function.27 Patients with disseminated MAI have been The relationship of AFB staining and culture results is shown to have at least partially reversible impairment of 24 of interest. Of the 15 cases in which both staining and T-cell-dependent immune functions ; this may be either culture were done, every case grew MAI, but only 10 a predisposing factor or a result of infection. stained for organisms. These included specimens with and The pathologic findings in patients with hematologic without definite granuloma formation. and other disorders did not appear distinguishable from In comparing the histopathology of these cases with those in patients without underlying disease. The asso­ that of M. tuberculosis infection, both similarities and ciation of disseminated MAI and hematopoietic disorders differences were apparent, depending on the tissue in­ has been documented previously, including hairy volved. The difference in tissue response was recognized cell leukemia'4 and chronic myelogenous leukemia as early as 195644 and may account, in part, for the con­ (CML)."'25 tinuing interest in this topic in the literature. Skin and The differential diagnosis of disseminated lesions caused bone specimens from patients with disseminated MAI by MAI depends on the clinical presentation and whether failed to show any evidence of caseous necrosis, well- AFB-packed, foamy histiocytes predominate. The findings formed granulomas, or giant cells, as is often seen in tu­ may suggest other infections, including tuberculosis,6 berculosis. MAI in these tissues is a deep-seated acute and other nontuberculous mycobacterioses,26 and other in­ chronic inflammatory process not suggestive of tubercu­ fectious or granulomatous diseases344'-46; histiocytic pro­ losis or other granulomatous diseases. The pathology of liferations, including disseminated histiocytosis x,143,46 MAI infection limited to the lungs23'38 and to the lymph eosinophilic granuloma,8 and Gaucher's disease,7 and nodes28 has been reviewed previously. Lymph nodes and malignancies, including malignant lymphoma, Hodgkin's pulmonary tissue in our patients showed granuloma for­ disease, and other primary or metastatic neoplasms.',32 mation and necrosis in both MAI infection and tuber­ In conclusion, MAI produces necrotizing inflammatory culosis. However, MAI infection tends to produce necrotic lesions distinguishable from tuberculosis in skin, bone, areas filled with inflammatory cells and nuclear debris and some lymph nodes. Adult patients without AIDS, rather than the acellular areas of caseation seen in tuber­ despite other causes of immunosuppression, have consis­ culosis. Furthermore, the palisaded rim of histiocytes and tent histopathologic findings that are markedly different numerous Langhan's type giant cells typical of tubercu­ from those in AIDS patients and from children with re­ losis were not seen in MAI infection. current infections. Such differences are likely due to host The pathology of disseminated MAI could not be com­ response, specifically macrophage-lymphocyte interac­ pared with that of other disseminated nontuberculous tions; however, evidence for the underlying defect is mycobacterioses, as too few cases of the latter were seen. scanty. 72 FARHI, MASON, AND HORSBURGH A.J.C.P. • January 1986 References 26. Mercyx JJ, Soule EH, Karlson AG: The histopathology of lesions caused by infection with unclassified acid-fast bacteria in man. 1. Bender BL, Yunis EJ: Disseminated nongranulomatous Mycobac­ Am J Clin Pathol 1964; 41:244-255 terium avium osteomyelitis. Hum Pathol 1980; 11:476-478 27. Miranda D, Vuletin JC, Kauffman SL: Disseminated histiocytosis 2. Bone M, Stableforth D: Miliary infection due to Mycobacterium and intestinal malakoplakia: Occurrence due to Mycobacterium avium-intracellulare. Tubercle 1981; 62:211-213 intracellulare infection. Arch Pathol Lab Med 1970; 103:302- 3. 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