Document jNQ1ORVXLvm9RnzZyo0Q2Qw6N

grief Reports BRIEF REPORTS are intended as short communications of clinical or technical observations of interest to readers of the Archives. They are usually limited to three illustnitinns and/or tables and to no more than ten pertinent references. In all other reyards the; should comply with the "Instructions for Authors" for the Archives. Systemic Talc Granulomatosis Associated With Disseminated Histoplasmosis in a Drug Abuser Luz S. Racela, MD; Christopher J. Papasian, PhD; Itaru Watanabe, MD; Douglas H. McGregor, MD; Saing H. Lee, MD; Robert Talley, MD A 32-year-old intravenous drug abuser was found to have systemic talc granuloma:osis and disseminated histoplasmosis. The clinicopathologic findings of this case upport the hypothesis that the patient was predisposed to disseminated histoplasmousby repeated intravenous talc administration. The effects of silica, a close relative of 'ilc, on macrophages and the role of macrophages in recovery from Histoplasma tjpsutatum infection are described. {Arch Pathol Lab Med 1988;112:557-560) phalation of Histoplasma capstdatum microconidia produces a pul monary infection that is followed by a "apid, transient, hematogenous dis^mination.' The infection is aborted ;ith little or no symptoms in the majority of patients. Factors predisosing people to systemic disease 'dude age extremes, hematologic malignancy, and iatrogenous or HiV'tdiated immunosuppression.'-1 In waling or healed primary histoplasmosis, degenerating fragments of the 'Acting organism are frequently 'served within macrophages.' In i'eepted for publication Feb 8. 1988. rom the Laboratory Service (Drs Racela. Watanabe. McGregor, and Lee), and `Medical Service (Dr Talley), Veterans ., visitation Medical Center, Kansas City, `l,e Department of Pathology and OncolVt ^ace*a* Papasian, Watanabe, McGregor. .t*e), and the Department of Medicine (Dr University of Kansas Medical Center. .'"City, Kan. 2**"1 requests to Laboratory Service (113). 7"** Administration Medical Center, -1801 .. Blvd. Kansas City, MO 84128 (Dr Papa- contrast, one striking histologic fea ture of disseminated histoplasmosis is the lack of intracellular fungus destruction by macrophages. Thus, it appears that the inability of macro phages to kill H capsulalum is a key element leading to disseminated dis ease.1 We recently cared for an intrave nous drug abuser with systemic talc granulomatosis and disseminated his toplasmosis. Obvious risk factors for disseminated histoplasmosis were lacking in this patient. Silica, which is closely related to talc, is known, how ever, to inhibit macrophage function.' We review the clinical and the patho logic features of this case and propose that talc predisposed the patient to disseminated histoplasmosis. REPORT OF A CASE A 32-year-old man was admitted to the Kansas City (Mo) Veterans Administra tion Medical Center with a fever of unknown duration. He admitted to alcohol abuse and he had been treated for narco lepsy for seven years with methylpheni- ilate hydrochloride i Ritalin) tablets, but he denied use oi nonprescribed drugs. On admission, he was well developed, fairly well nourished, and in no acute distress, but he had a temperature of 37.5*C. Pertinent physical findings in cluded hepatomegaly to 5 cm below the right costal arch, bilateral axillary lymphadenopathy. and 3+ pitting edema in both extremities. There were needle tracks, both new and scarred, bilaterally at the antecubital fossae. Ophthalmologic examination revealed tiny crystals in both retinas. The remaining physical findings were unremarkable. Chest roentgenography showed multiple small densities in both lung fields. A urine drug screen was negative. Serum protein electrophoresis showed a polyclonal hyper gammaglobulinemia. Relevant laboratory findings included: hemoglobin, 79 g/L (7.9 g/dL); white blood cell count, 9.3 X 10VL (9300/mm1) (0.41 [41") polymorphonucle ar leukocytes. 0.24 [24% ] lymphocytes. 0.24 [24% ] atypical lymphocytes, 0.03(3% ] band cells, and 0.08 (8%) monocytes); aspartate aminotransferase. 30a IU; serum gammaglutamyl transpeptidase, 124 ID; alanine aminotransferase. 60 IU: total serum bili rubin, 10 wmol/L (0.6 mg/dL); ethanol, 029 mmol/L) 137 mg/dL; total serum protein, (89 g/L) 8.9 g/dL; albumin. (38 g/L) 3.8 g/dL; globulin, (510 mg/dL) 5.1 g/L; hepatitis B core antibody, positive; hepatitis B surface antigen and antibody, negative; and cytomegalovirus indirect immunofluorescence antibody titer, 1:512. Histologic examination of a bone mar row biopsy specimen revealed multiple noncaseating granulomas of varying size. '"'"holLab Med--Vol 112. May 1988 Granulomalosis--Racela et al 557 ^ >yy`:Ji, V:*rr-' ft -.:: *1 ...;-i i $ 4 Ii ^ ^ **> *" . f * ' e *1r^ - ~ t? .y*5 -, **. ve* t*h . *j# & &**^ -f &<r>N &. W .*?.* * a* i? * * v^s Fig I.--Noncasealing bone marrow granuloma (hematoxylin-eosln, X280). Inset. Polarization microscopy showing birefrrngent crystals in bone marrow granuloma (X280). They consisted primarily of multinucleated giant and epithelioid celts surrounded by lymphocytes (Fig 1). Fibrosis was not noted in any of the bone marrow granulo mas. Birefringent needle-shaped crystals varying from 1 to 2 pm in length were present within giant cells (Fig 1). A Grocott's mcthenamine silver stain revealed few intracellular yeasts within multinucleated giant cells (Fig 21. Viral inclusions were not noted, and viral cultures were negative. Culture of the bone marrow biop sy specimen produced H capsulatum. This identification was confirmed by production of tuberculate macroconidia at room tem perature and conversion to the yeast phase at 37"C. A histoplasmin skin test induced a strongly positive response. Complement fixing antibody titers to histoplasmin and yeast phase antigens were negative on initial presentation: follow-up tests were not performed. A liver biopsy specimen showed chronic active hepatitis with portal and intralobu lar noncasealing granulomas containing the crystals described above, and occasion al yeasts. Immunohistochemicai peroxi dase-antiperoxidase staining for hepatitis B surface antigen was negative. An axil lary lymph node biopsy specimen showed no granuloma. There was, however, marked proliferation of sinus histiocytes, some of which contained melanin and the birefringent crystals described above. Histoplusniu capsulatum was recovered from the lymph node biopsy cultures. Viral inclusions were not noted in either the lymph node or liver biopsy specimen and viral cultures of the lymph node were negative. Electron microscopy of the bone marrow and the lymph node biopsy specimens, revealed crystals in the cytoplasm of multinucleated giant cells and macrophages (Fig 3). These crystals most closely resem bled talc. In view of the patient's disseminated histoplasmosis and physical findings indi cating intravenous drug use, peripheral T-cell subsets and T-cell function were assessed by flow cytometry and mitogen stimulation. At the time of these studies the total leukocyte count was 10 x 10VL (10000/mm1): lymphocytes composed 0.57 (57%) 5.7 X lO'/l, <5700/mm`) of the total leukocytes. Total T-cells (T,,), T,,lr,, (T.). and T. ,,..... (T.) cells composed 0.89 (89% 1 5.1X10VL (5073/mm1), 0.31 (31.4%) 1.8X107L (1790/mm1), and 0.51 (50.6%) 2.9 x 10VL (2884/mm1), respectively of the peripheral lymphocytes. The T.:Ti ratio was depressed (0.02) due to an increased number of suppressor cells: total T- and T^n-cell numbers were within normal limits. The blastogenic responses to phyto hemagglutinin and concanavalin A (Con A) was moderately decreased. Intravenous therapy with amphotericin B was initiated, and continued until the patient received a total of 1.94 g. The H capsulutfttrt infection w.i.s iri,- the patient has survived for ui,-r t|, years, without recurrence, since corn;,;,, ing his course of antifungal therm. COMMENT Visceral granulomatosis uncommon in intravenous drug ahu,. ers. Granulomas occur most frequent, ly in the lungs; however, intravenou. drug abusers with hepatic and s\,. temic granulomatosis have also been reported.' The granulomas form j.~ response to particulate matter, usual ly talc, used as filler for phat- . , . cal agents intended for or he, administered intravenously nous talc administration can induce fibrotic, angiothrombotic, an.i hypertensive pulmonary changes, and may eventually lead to cardiorespira tory insufficiency anil death.' Meta:,, done hydrochloride, morphine sulfa',-, methylphenidate hydrochloride, iri- pelennamine hydrochloride I pm poxyphene hydrochloride am pies of pharmaceuticals .. ,-nt . "cut" with talc for intravenous u?e. Although the patient denied intra venous drug use. we assume that methylphenidate was administered intravenously because this agent i- frequently cut with talc, has been associated with talc granulomas, na.- available to the patient, and the patient had physical signs -raie- nous drug abuse. Use of -Iruc- could neither be substantiated nur refuted. The affects of talc (magnesium sili cate) on the immune system have n.-i been well studied. Silica (silicon di\- ide), which is closely related to talc- inhibits macrophage function and been associated with an inereim-- incidence and severity ' to Mycobacterium lul ' increased incidence of un i. ' also seen in talc miners. Experimental mycobacterial m1,1 tion is potentiated by silica inject or by inhalation of silica dust. M->- Testations of experimental mycobai -< rial infection potentiated by ' exposure include increased care establishing infection. '*'r : " counts of viable or. ' increased lethality.' The ; '11 ica on M tuberculosis illicit",n " attributed to its direct inhibitor 558 Arch Pathol Lab Med--Volt 12. May 1988 Granulomatosis--' I- K-\ - 4 3 r -<4v A* - * * V *^,**. sr: > -` \ * > .* -^r #, 5 vv "* Tt/* 1 ^ r /> -j .v -4 *- w\< V*- c .V' X' B* r ,,' *.v;^., * Tx: 'f> * a V^ J-'-kAr < \i. BB1 Fig 3.--Electron-microscopic examination revealing needle-shaped crystals (arrows) in lymph node macrophages (X22 500). -g 2.--Bone marrow giant cells with intracellular yeasts (Grocott's methenamine silvar stain. 280). ixic effects on mononuclear phagovtes.* At sublethal doses, silica markily increases the multiplication of M berculosis in long-term peritoneal crophage cultures in a dose-depen:<nt manner.1 Potentiation of mycoicterial growth in vivo is also dose-' Impendent. Humans exposed to silica fat have a much higher incidence of iberculosis than nonsilicotic persons torn similar geographic locales.* In ct, prior to the availability of anti'ycobacterial chemotherapy, tuberlosis was the major cause of death i classic silicosis.* Additionally, silitic humans have a less favorable tponse to antimycobacterial chemo"trapy than nonsilicotic humans.* A cent article described an intrave- drug abuser with disseminated "* granulomatosis and miliary ^rculosis.1 The authors proposed 11 the substantial phagocytosis of c crystals by macrophages facili d the spread of M tuberculosis. ;mmune lymphocytes from H capKiim-infected mice must activate prophages in order for the phago- to kill endocytosed fungi.* This r*tion is at least partially attrib- , to soluble factors, perhaps '^ing interferon gamma, released ntmune T-lymphocytes.' In sys- temic histoplasmosis, mononuclear phagocytes of the reticuloendothelial system cannot kill engulfed fungi.1 It is unclear whether the lack of intra cellular killing is due to an intrinsical ly inadequate macrophage digestive mechanism or to a failure of lympho cytes to activate macrophages. Re gardless of mechanism, decreased killing of yeasts by macrophages increases the likelihood of systemic disease following infection with H capsulatum. Inbred or random-bred mice inoculated intravenously with silica 1, 14, or 21 days before exposure to H capsulatum showed greater sus ceptibility to infection than mice not treated with silica.10 Manifestations of increased susceptibility included an increase in the number of viable organisms recovered from spleens of killed mice, lower body weights, and increased mortality. Intravenous sili ca administration also decreased the blastogenic response of mouse splenocytes to T-cell mitogens (ie, Con A and phytohemagglutinin [PHA]), but not to be a B-cell mitogen (ie, lipopolysaccharide).'The blastogenic response of T-cells to PHA and Con A is macro phage-dependent, whereas, the re sponse of B-cells to lipopolysaccharide is macrophage-independent. This, in conjunction with the in vitro finding that silica particles were toxic to mac rophages but not lymphocytes, indi cated that silica inhibited T-cell blastogenesis indirectly via depressing macrophage functions.'0 Thus, silica increased the severity of histoplasmo sis in infected mice by: (1) inhibiting macrophages effector mechanisms (ie, phagocytosis and intracellular kill ing); and (2) inhibiting macrophagedependent immune functions (ie, Tcell blastogenesis leading to macro phage activation). We have described the case of an intravenous drug abuser with system ic talc granulomatosis and dissemi nated histoplasmosis. He was not iatrogenically immunosuppressed, he did not have a hematologic malignancy, and he was not predisposed to dissem inated histoplasmosis by age. Al though he was at high risk for devel oping acquired immunodeficiency syndrome (AIDS) or AIDS-related complex (ARC), immunologic studies were not consistent with this diagno sis. The T,,,,,, (T,): Ttwra, (T,) ratio was slightly depressed (0.62) due to an elevated number of T,-cells; total T and T,, cell numbers were normal. This finding is consistent with dissemi nated histoplasmosis." In AIDS and ARC, the aberrant T,:T, ratio is usual ly due to a decrease in the number of T, cells." The patient also had a mod erately depressed T-cell blastogenic response to PHA and Con A. The ;,p*lhotLab Med--Vol 112. May 1988 Granulomatosis---Raceia et at SS9 decrease was probably due to systemic fungal infection, or perhaps, dissemi nated talc granulomatosis.Addition al indications that the patient did not have AIDS or ARC were a markedly positive histoplasmin skin test, recov ery from histoplasmosis with ampho tericin B therapy, and subsequent sur vival for over three years. He has been seen as an outpatient on several occa sions over the three years and showed no physical signs of AIDS, ARC, or opportunistic infections. Thus, al though the patient was not tested for antibody to HIV, it is clear that he was not predisposed to disseminated histoplasmosis by HIV infection.*12 Phagocytosis and intracellular killing of yeasts by mononuclear phagocytes of the reticuloendothelial system are crucial to an uneventful, self-limited illness following H capsulutum infec tion.1 Silica, which is closely related to talc, is directly toxic to macrophages; inhalation or intravenous exposure to silica lowers resistance to histoplas mosis, tuberculosis, and other infec tious diseases in which macrophage function is crucial." We propose that the patient lowered his macrophagemediated resistance to H capsidntum infection by repeated intravenous talc administration. We thank William Bopp. Willavieve Gayiien, and the histology section at Kansas City Veter ans Administration Medical Center for technical assistance. Brenda Adams and Jamesetta M. Stewart for clerical assistance, and Jacob K. Frenkel. MD for constructively criticizing the manuscript. References 1. Goodwin RA. Shapiro JL, Thurman GH. et al: Disseminated histoplasmosis: Clinical and pathologic correlations. Medicine 19S0:59:l-33. 2. Taylor MN. Baddour LM. Alexander JR: Disseminated histoplasmosis associated with the acquired immune deficiency svndrome Am J Med 19$4,77.579-$S0. 3 Wheat LJ. Slama TG. Norton JA. et at: Risk l.u tors fur ili<>M>min.itvl or f.it.ii U" hit. rn \l,,i V.iHZUb ........ 1 llltcr ! I,. McRcvnoiiis fl \ I mnmn.<i,,V](. gy <>i siitc.i. CltC Crit Iti'v Trtrni 319 ' a Manani-Constantini R. Jjiinoit. son FB Systemic visceral talc gra t( ` associated with miharv tunerculoM^ k (j addict. .4/n J Clin Pathol 19S2.7S'7,'n.",-7' . * ' 6. Snider DE: The relationship hi*u.rrn r culosis and silicosis. Am R?v Resptr [),,, LIS. 455-459 7. Rubino GF. Scansetti G. Piolatto G Mortality study of talc miners and mill..J Occnp Med I976.1S 1S6-193. S. Allison AC. Hard PD. Potentiation by mIuof the growth of Mycobucterium macrophage cultures. Br J Exp Pun,,,; ..'w 49-465-476 9. Wu-Hsieh G, Howard DH D . l1>n growth of Hisloplasma capsulntm w kine-stimulated macrophages ./ / 132:2593-2597 10. Von Behren LA, Chaudhary S. Knanlon et al: Eireci of silica on the susceptibiim (,f r; to experimental histoplasmosis J Rtneui.* .. thelSoc 19S3;34:99-lll. 11- Payan DC. Wheat LJ. Brahmi Z. ,t j Changes in immunoregulatory lympnoc.ue i-.j.. lations in patients with histoplasmosis / < Immunol 19S4;4'9S-107. 12 Siegal FP: Immune function ,m.| ii-f,-. tion in AIDS. Srnun Oncol 19S4.1I g- Cystic Hypersecretory Duct Carcinoma of the Breast Report of a Case. With Fine-Needle Aspiration Jean M. Colandrea, MD; Barry M. Shmookler, MD; Gerard J. O'Dowd, MD; Max H. Cohen, MD, PhD A patient with a recently described rare histologic variant of ductal carcinoma of the breast, so-called cystic hypersecretory duct carcinoma, is described. The findings on line-needle aspiration biopsy, and to our knowledge, the first cytologic study of this entity reported in the literature, are described and ditferentiated from mucinous carcinoma and benign mucoceleiike lesions. The histologic differential diagnosis, with an emphasis on benign lesions that may have a predominant cystic component, is also discussed. [Arch Pathol Lab Med 1988; 112:560-563) r^ystic hypersecetory duct carcinoma (CHDC) of the breast, a rare his tologic variant of intraductal carcino ma recently described by Rosen,1 is characterized by the formation of variably sized cysts that contain an eosinophilic secretory product remi niscent of thyroid colloid, and by micropapillary carcinoma occurring both within some, but not all, of these cysts, as well as in adjacent nondistended ducts. We describe a patient Accepted for publication Auk 6. 1987. From the Departments of Pathology (Drs Col andrea. Shmookler, and O'Dowd) and Surgery (Dr Cohen), The Washington Hospital Center. 110 Irving St NW, Washington. DC 20010. Reprint requests to Department of Pathology, Washington Hospital Center. 110 Irving St NW, Washington DC. 20010 (Dr Colandrea). with CHDC, who had initially under gone biopsy and was diagnosed . having benign fibrocystic disease 1981. Five years later, in r.'bti. tf' lesion recurredlocally and was era., ated by fine-needle aspi: 1`"i ^ ^ ' A subsequent incisiona; -> ^i1" . men confirmed the diagnosis of l ` and the patient underwent nio*l:'> radical mastectomy. To our kn<**| edge, this is the first description FNA cytologic features of CHDt its distinction from both mucin' (colloid) carcinoma and benign m-> celelike lesions. In addition, the h'--^ logic differential diagnosis of l ^ ^ will be discussed, par ir'> . its deceptively blanu 'u" '' i. . appearance can be contused Al " variety of benign breast disean'r I j r-J i j e/tzed <large< I -o dist -raefunr .-'acts on Si ;*fipnen ; XA. Xr t 67-y roe age al cstr -rented iidtenii 'psy sc rmed at * benigr aminati 'll scar `e left bn ~ph noc * masses ~?h nor la. Res ' 'IC3I ex mmogra :>m bill i an irr >r outei * border mi mcalcifir cecomrr 'nmetry * f inc 1 tide 01 '> relate, j **a nor clinic '"The fi 'due to 'obuleso '. I*v*alet 'tecreti ** biopsy -rs<cretor ^ njaste momy s mi 560 Arch Pathol Lab Med--Vol 112. May 1986 Breast Carcinoma-- v- Lat