Pneumocystis Carinii Infection of the Small Intestine in ...

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lesion and adjacent enlarged mesenteric lymph nodes were removed, and the patient was treated for three weeks with intravenous trimetho- prim (20 mg/kg/D) ...
Single Case Reports Pneumocystis Carinii Infection of the Small Intestine in a Patient with Acquired Immune Deficiency Syndrome TIMOTHY R. CARTER, M.D., PHILIP H. COOPER, M.D., WILLIAM A. PETRI, JR., M.D., C. KURTIS KIM, M.D., PETER D. WALZER, M.D., AND RICHARD L. GUERRANT, M.D.

PNEUMOCYSTIS CARINII is a well known cause of pneumonitis in immunocompromised hosts. The fact that P. carinii can also affect extrapulmonary sites is less well recognized. Prior to the advent of the acquired immune deficiency syndrome (AIDS), there were only isolated reports of extrapulmonary pneumocystos j s 1-4,8.9,13,15,18-20 Subsequently, a small number of relatively brief descriptions of extrapulmonary infection with P. carinii in AIDS patients appeared in the literature.6'7"'16'21 We describe an AIDS patient with symptomatic P. carinii infection of the small intestine and review the literature concerning extrapulmonary pneu-

Received May 13, 1987; accepted for publication July 24, 1987. Supported in part by the Lucille P. Markey Charitable Trust and by the Medical Research Service of the Veterans Administration and Public Health Service Contract NOl-AI-42548, National Institutes of Health. Address reprint requests to Dr. Cooper: Department of Pathology, Box 214, University of Virginia Medical Center, Charlottesville, Virginia 22901.

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Departments of Pathology and Internal Medicine (Divisions of Infectious Diseases and Geographic Medicine), University of Virginia, Charlottesville, Virginia and Departments of Pathology and Laboratory Medicine and Internal Medicine (Division of Infectious Diseases), University of Cincinnati, and the Veterans Administration Medical Center, Cincinnati, Ohio

mocystosis. An immunoperoxidase technique for the identification of P. carinii was employed to further substantiate the diagnosis. Report of a Case A 35-year-old white male was admitted to the University of Virginia Hospital with an acute abdomen. He had been diagnosed as having AIDS-related complex six months previously based on the presence of diffuse lymphadenopathy and a Western blot hybridization study that was positive for antibodies to the human immune deficiency virus. During the time prior to admission, he had persistent dysphagia, but two barium swallow x-rays were normal. The patient otherwise remained well, without fever or weight loss, until one day prior to admission when he noted the abrupt onset of abdominal pain, most marked in the left lower quadrant. There was no nausea, vomiting, or diarrhea. The patient was treated with antibiotics at a nearby hospital for a presumptive diagnosis of diverticulitis and was then transferred to the University of Virginia Hospital. On admission, the patient's temperature was 37.5 °C. He was in moderate distress and complained of abdominal pain. Physical examination revealed oral thrush, axillary and inguinal lymphadenopathy, and left lower quadrant abdominal rebound tenderness and guarding. Examination of the heart and lungs was normal. Stool was negative for occult blood. Chest x-ray showed small nodular densities in the right upper lobe consistent with old granulomatous disease. There was no free air under the diaphragm. An abdominal x-ray demonstrated a nonspecific bowel gas pattern. Exploratory laparotomy disclosed a mass in the small intestine, 75 cm proximal to the ileocecal valve. The lesion and adjacent enlarged mesenteric lymph nodes were removed, and the patient was treated for three weeks with intravenous trimethoprim (20 mg/kg/D) and sulfamethoxazole. Recovery was uneventful, and, except for persistent lymphadenopathy, the patient appeared well, three months following surgery. The chest x-ray remained unchanged, and a silver stain of one sputum specimen was negative for P. carinii.

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The authors describe a patient with acquired immune deficiency syndrome (AIDS) who presented with an acute abdomen. A plaque-like tumor of the small intestine was resected and found to consist of masses of Pneumocystis carinii organisms. The organisms also exhibited a perivascular and intravascular distribution. Identical changes were found in regional lymph nodes. In addition to silver stains and electron microscopy, an immunohistochemical method for the demonstration of P. carinii was employed. The technique may have advantages over silver staining, as it identifies trophozoites in addition to cysts. A review of the literature concerning extraplumonary pneumocystosis indicates that affected patients nearly always have concurrent pulmonary infection. The pattern of organ involvement and the finding of perivascular and intravascular organisms are consistent with lymphatic or hematogenous dissemination from the pulmonary focus. Pulmonary pneumocystosis was not documented in the patient described herein, although there were radiographic densities in one pulmonary lobe. (Key words: Pneumocystis carinii; Extrapulmonary pneumocystosis; Small intestine; Immunoperoxidase technique) Am J Clin Pathol 1988; 89: 679-683

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Immunohistochemical Study Immunoperoxidase staining was performed with the avidin-biotin method employing reagents and procedures similar to those of an earlier study.14 Antisera to rat P. carinii and human P. carinii from a non-AIDS FIG. 2 (lower). Cysts of Pneumocystis carinii. Methenamine silver patient were produced in rabbits according to proce(X790). Inset: Foamy material and cysts within thin-walled vessel. Methenamine silver (X375). dures described previously.1722"24 The antisera were adsorbed with normal rat or human lung prior to use and were judged to be specific for P. carinii when tested for Pathologic Observations cross-reactivity with a variety of bacteria and fungi. Sections were deparafnnized and rehydrated. They were The resected segment of intestine contained a well then treated with two percent hydrogen peroxide, incucircumscribed, 4 X 3 X 1.8-cm, intramural, partially bated with rabbit antiserum to rat P. carinii (1:16) or to ulcerated, plaque-like mass. The cut surface disclosed human P. carinii (1:80) for 30 minutes at room temperred-tan and yellow, friable, grossly calcified material. ature, and then incubated with biotin labeled goat antiRegional mesenteric lymph nodes ranged in size from rabbit IgG followed by avidin-biotin-peroxidase com0.5-1.2 cm and were extensively replaced by nodules of plex. The slides were washed, incubated with diaminosimilar substance. benzidine, and counterstained with hematoxylin. Microscopically, the intestinal lesion (Fig. 1) was The foamy, honeycombed material, representing composed of confluent lakes and smaller perivascular packed P. carinii organisms, was strongly positive when patches of light eosinophilic, honeycombed or foamyrabbit antiserum to human P. carinii was used as the appearing, focally calcified material that extended from primary antibody (Fig. 4). Both cysts and trophozoites the muscularis mucosae to the serosa. It dissected norFIG. 1 (upper). Confluent lakes of eosinophilic, foamy, focally calcified material abut muscularis mucosae. Hematoxylin and eosin (X65). Inset: Perivascular foamy material. Hematoxylin and eosin (X375).

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mal tissue elements, and many fields contained only isolated remnants of smooth muscle or fibrovascular tissue. The foamy substance abutted, but did not breach, the muscularis mucosae. Lymphocytes and plasma cells were present around intact blood vessels, and a few vessel lumens contained foamy material. Overlying mucosa showed minimal acute inflammation as well as sharply marginated, full-thickness ulcers. Regional lymph nodes were replaced by eosinophilic, calcified material identical to that observed in the intestine. In one field, the deposit was bordered by a layer of mono- and multinucleated epithelioid histiocytes. Radiographs of tissue blocks demonstrated abundant stippled calcification. Hematoxylin and eosin stains demonstrated numerous basophilic bodies, less than 1 n in diameter, throughout the foamy material. Methenamine silver stains revealed characteristic forms of P. carinii, including a few within vessel lumens (Fig. 2). No acid fast bacteria, fungi, or viral inclusions were present. The mucosa contained no Cryptosporidia. Fibrinopurulent exudate at ulcer bases and in the subserosa contained groups of gram-positive rods and occasional gram-negative rods. Ultrastructural examination confirmed that the foamy, honeycombed material was composed of packed organisms with sparse intervening collagen (Fig. 3). Numerous trophozoites, cysts, intermediate forms, and empty cysts were admixed with a scanty amount of cellular debris. Filopodia were present around the organisms, including cysts and trophozoites.

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were stained, but they could not be clearly distinguished from each other. No staining occurred with rabbit antiserum to rat P. carinii. As controls, P. carinii in lung sections from patients with pulmonary pneumocystosis stained intensely, but no staining occurred with immune serum in normal lungs or when preimmune rabbit serum was substituted for the primary antibody. Discussion

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Excluding individuals with AIDS who will be discussed below, extrapulmonary involvement by P. carinii has been reported in 14 patients.1-4'8-91315,18"20 With one exception,1 all had either primary or secondary immunodeficiency. Sites of extrapulmonary involvement included hilar or mediastinal lymph nodes (nine patients), retroperitoneal lymph nodes (one patient), spleen (five patients), bone marrow (five patients), thymus (two patients), and liver (three patients). Two patients had extensive multiorgan disease, with additional sites of involvement that included the heart, pericardium, stomach, small intestine, ascending colon, pancreas, homograft kidney, periureteral retroperitoneum, hard palate, adrenal gland, and thyroid gland.219 With one exception,20 all of the patients had clinically evident lung disease. A premortem diagnosis of P. carinii was made by lung biopsy in seven cases and at autopsy in all cases. With the exception of three patients in whom P. carinii was found in a bone marrow biopsy shortly before death, 220 the extrapulmonary involvement was only recognized at postmortem examination. An additional five examples of extrapulmonary P. carinii infection have been reported in AIDS patients.6'7"'16'21 Affected individuals ranged in age from 29 to 42 years, and all were males. One patient was noted to have multiple cotton wool spots on both retinae several months before death." He was unsuccessfully treated for P. carinii pneumonia, and at autopsy, P. carinii was found in a retina by electron microscopy. P. carinii was found in duodenal and esophageal biopsies from a patient with Pneumocystis pneumonia and dysphagia.7 Autopsy revealed extensive pneumocystosis that involved the esophagus, heart, lymph nodes, spleen, pancreas, liver, stomach, small intestine, appendix, kidneys, bone marrow, and adrenal glands. In an additional patient with splenomegaly and lymphadenopathy, premortem study of spleen, liver, and lymph nodes documented extrapulmonary pneumocystosis.16 Pulmonary and disseminated pneumocystosis were found at autopsy. Two other AIDS patients presented with gradual hearing loss.6,21 One had 2 X 2-cm polyps in both external auditory canals, with unilateral middle ear involvement,6 and the other had a unilateral, 0.3 X 0.5-cm polyp at the junction of the external auditory canal and

FlG. 3 (upper). Ultrastructurally, foamy material was composed of masses of Pneumocystis carinii. Cyst (upper left) and trophozoites are mixed with scant intervening collagen. Filopodia are present around the organisms (X15,800). FIG. 4 (lower). Immunoperoxidase staining of foamy material using polyclonal antibody to human Pneumocystis carinii. Notice similar positively staining material within vessel (upper left) (X200).

pars flaccida.21 In each instance, biopsy of a lesion contained P. carinii. One of the patients developed Pneumocystis pneumonia one month later.6 The other re-

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It is also of interest, and of potential diagnostic value, that the gross appearances of extrapulmonary pneumocystosis are similar to those of P. carinii pneumonia. Consistently described features include coalescent patches of grayish white or yellow-red, soft, cheesy, necrotic-appearing material that range in size from a few millimeters to several centimeters.1"4,9,13,16 Grossly evident calcification, as observed in our case, was mentioned in one previous report of extrapulmonary pneumocystosis.13 Radiographs of tissue blocks from our patient exhibited stippled calcification. Calcification could not be appreciated on routine preoperative abdominal films but might have been visible with more sophisticated methods. Calcification is not a usual feature of other opportunistic infections (including, apparently, histoplasmosis25) or neoplasms associated with AIDS. Its detection in an extrapulmonary lesion in an AIDS patient may be a diagnostic clue to P. carinii infection. Immunoperoxidase staining of P. carinii has been described on only two prior occasions to the best of our knowledge.12,14 This technique should prove useful for both retrospective and prospective screening of large numbers of specimens for the presence of P. carinii. It stains organisms in all stages of their life cycle, whereas methenamine silver stains only the cysts. The technique may aid in confirming the diagnosis in controversial cases or when only a few silver-positive organisms are present that might be confused with fungi. Moreover, this method has potential for comparing the antigenic

characteristics of different clinical isolates. Although the antisera used herein were polyclonal, a monoclonal antibody to human P. carinii has recently been developed and used to detect the organism by immunofluorescence in bronchoalveolar lavage fluid.10 Nearly all reported patients with extrapulmonary pneumocystosis had concurrent pulmonary infection, and it seems likely that dissemination occurred from the pulmonary focus. The pattern of organ involvement and the presence of perivascular and intravascular organisms observed in several cases support lymphatic or hematogenous routes of dissemination. Pulmonary disease was not clinically evident in one patient with an otic polyp due to P. carinii,2^ but the period of follow-up was not stated. Moreover, our patient had nodular pulmonary densities of undetermined cause. The lungs, therefore, remain as a possible source for dissemination of P. carinii in both of these cases. The presence of microorganisms in gastric contents of patients with pulmonary pneumocystosis5 suggests that swallowed organisms could also represent a mechanism for infection of the gastrointestinal tract. There was no direct evidence for this in our patient, however. In light of the increasing number of AIDS patients, additional cases of extrapulmonary pneumocystosis will undoubtedly be documented in the near future. References 1. Anderson CD, Barrie HJ: Fatal Pneumocystis pneumonia in an adult: Report of a case. Am J Clin Pathol 1960;34:365-370. 2. Awen CF, Baltzan MA: Systemic dissemination of Pneumocystis carinii pneumonia. Can Med Assoc J 1971;104:809-812. 3. Barnett RN, Hull JG, Vortel V, Schwarz J: Pneumocystis carinii in lymph nodes and spleen. Arch Pathol 1969;88:175-180. 4. Burke BA, Good RA: Pneumocystis carinii infection. Medicine 1973;52:23-51. 5. Chan H, Pifer L, Hughes WT, Feldman S, Pearson TA, Woods D: Comparison of gastric contents to pulmonary aspirates for the cytologic diagnosis of Pneumocystis carinii pneumonia. J Pediatr 1977;90:243-244. 6. Coulman CU, Greene I, Archibald RWR: Cutaneous pneumocystosis. Ann Intern Med 1987;106:396-398. 7. Grimes MM, LaPook JD, Bar MH, Wasserman HS, Dwork A: Disseminated Pneumocystis carinii infection in a patient with acquired immunodeficiency syndrome. Hum Pathol 1987;18:307-308. 8. Henderson DW, Humeniuk V, Meadows R, Forbes IJ: Pneumocystis carinii pneumonia with vascular and lymph nodal involvement. Pathology 1974;6:235-241. 9. Jarnum S, Rasmussen EF, Ohlsen AS, Sorensen AWS: Generalized Pneumocystis carinii infection with severe idiopathic hypoproteinemia. Ann Intern Med 1968;68:138-145. 10. Kovacs JA, Swan JC, Shelhamer J, et al: Prospective evaluation of a monoclonal antibody in diagnosis of Pneumocystis carinii pneumonia. Lancet 1986;2:1-3. 11. Kwok S, O'Donnell JJ, Wood IS: Retinal cotton-wool spots in a patient with Pneumocystis carinii infection. N Engl J Med 1982;307:184-185. 12. Lee C-H, Bolinger CD, Bartlett MS, Kohler RB, Wilde CE III, Smith JW: Production of monoclonal antibody against Pneu-

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mained free of lung disease for an unspecified period.21 The otic polyps responded to specific therapy for P. carina. The diagnosis of extrapulmonary pneumocystosis depends on a characteristic constellation of histologic findings in hematoxylin and eosin-stained sections, supported by appropriate special studies. Thirteen reports included some microscopic detail,1"4,6""9'131619'21 and all described foamy, honeycombed, or reticulated eosinophilic material within affected tissue. Other features mentioned included a patchy and confluent distribution of the material2,813 and numerous small dark bodies1,313 and calcification3,4,13 within it. Perivascular wreathing by exudate was noted in two cases,6,8 and foamy material containing organisms was noted within vessel walls or lumens in four instances.2,6"8 The inflammatory response has been variable and nonspecific, but a histiocytic3 or granulomatous13,21 reaction was observed in three cases. Visualization of the organisms with special stains, the most useful of which is the methenamine silver, confirms the diagnosis. Ultrastructural examination is not ordinarily necessary, although, infivereports, including our own,2,1116,21 electron microscopy was performed for complete documentation.

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15. 16.

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mocyslis carinii by using a hybrid of rat spleen and mouse myeloma cells. J Clin Microbiol 1986;23:505-508. LeGolvan DP, Heidelberger KP: Disseminated, granulomatous Pneumocystis carinii pneumonia. Arch Pathol 1973;95:344348. Levin M, McLeod R, Young Q, et al: Pneumocystis pneumonia: Importance of gallium scan for early diagnosis and description of a new immunoperoxidase technique to demonstrate Pneumocystis carinii. Am Rev Respir Dis 1983;128:182-185. Livingstone CS: Pneumocystis pneumonia occurring in a family with agammaglobulinemia. Can Med Assoc J 1964,90:12231225. Macher AM, Bardenstein DS, Zimmerman LE, et al: Pneumocystis carinii choroiditis in a male homosexual with AIDS and disseminated pulmonary and extrapulmonary P. carinii infection. N Engl J Med 1987;316:1092. Milder JE, Walzer PD, Coonrod JD, Rutledge ME: Comparison of histological and immunological techniques for detection of Pneumocystis carinii in rat bronchial lavage fluid. J Clin Microbiol 1980;11:409-417. Price RA, Hughes WT: Histopathology of Pneumocystis carinii

19. 20. 21.

22. 23. 24. 25.

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infestation and infection in malignant disease in childhood. Hum Pathol 1974;5:737-752. Rahimi SA: Disseminated Pneumocystis carinii in thymic alymphoplasia. Arch Pathol 1974;97:162-165. Rossi J-F, Dubois A, Bengler C, et al: Pneumocystis carinii in bone marrow. Ann Intern Med 1985;102:868. Schinella RA, Breda SD, Hammerschlag PE: Otic infection due to Pneumocystis carinii in an apparently healthy man with antibody to the human immunodeficiency virus. Ann Intern Med 1987;106:399-400. Walzer PD, Rutledge ME, Yoneda K: A new method of separating Pneumocystis carinii from infected lung tissue. Exp Parasitol 1979;47:356-368. Walzer PD, Rutledge ME: Comparison of rat, mouse, and human Pneumocystis carinii by immunofluorescence. J Infect Dis 1980;142:449. Walzer PD, Linke MJ: A comparison of the antigenic characteristics of rat and human Pneumocystis carinii by immunoblotting. J Immunol 1987;138:2257-2265. Wheat LJ, Slama TG, Zeckel ML: Histoplasmosis in the acquired immune deficiency syndrome. Am J Med 1985;78:203-210.

MARK L. BUNKER, M.B., B.CH., LEE CHEWNING, D.M.D., SCOTT E. WANG, M.D., AND MORRIS A. GORDON, PH.D.

The authors report the first human case (to our knowledge) of infection of the oral mucosa by Dermatophilus congolensis. Septate branching filaments morphologically identical to those of D. congolensis were identified in the lingual epithelium of a male homosexual employed as an animal handler. This actinomycete is the cause of dermatophilosis, a proliferative exudative dermatitis affecting many animal species. Clinical features suggested "hairy" leukoplakia (HL), a hyperkeratotic tongue lesion for which human papillomavirus (HPV) and EpsteinBarr virus (EBV) have been implicated as etiologic agents. Immunoperoxidase staining for HPV capsid antigen was negative. Direct immunofluorescent staining with a conjugate specific for D. congolensis identified the bacterial structures as those of this species while excluding morphologically similar organisms. (Key words: Dermatophilus; Hairy leukoplakia; Acquired immune deficiency syndrome; Immunofluorescence; Immunohistochemistry) Am J Clin Pathol 1988;89:683-687 DERMA TOPHILUS CONGOLENSIS is an actinomycete of worldwide distribution which causes a proliferative exudative dermatitis in a broad range of animal hosts, particularly sheep, cattle and horses. 8 The result-

Received June 12, 1987; received revised manuscript and accepted for publication July 29, 1987. Address reprint requests to Dr. Bunker: Department of Pathology, Presbyterian University Hospital, DeSoto at O'Hara Streets, Pittsburgh, Pennsylvania 15213.

Departments of Surgical Pathology and Oral Surgery, Allegheny General Hospital, Pittsburgh, Pennsylvania; and Wadsworth Center for Laboratories and Research, New York State Department of Health, Albany, New York

ing affliction, dermatophilosis, (syn. streptotrichosis, lumpy wool, strawberry foot rot) may be transmitted to man by direct contact with infected animals. 5 1 2 Dermatophilosis manifests itself histologically by epidermal acanthosis, hyperkeratosis, and parakeratosis, associated with hydropic degeneration or ballooning of keratinocytes. 1 6 1 8 An exudate containing acute inflammatory cells is usually present between the dermis and the overlying infected epidermis. 19 The microscopic appearance of the organism in tissue sections takes the form of basophilic branching filaments which undergo division along both longitudinal and transverse axes, ultimately forming packets of coccoid zoospores. 8 An organism identified on morphologic grounds as D. congolensis has been observed in the margins of lesions of pitted keratolysis (PK), a usually asymptomatic condition characterized by multifocal sharply punched-out "pits" within the stratum corneum of the soles of the feet. 20 Recently an organism resembling D. congolensis

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Dermatophilus congolensis and Hairy Leukoplakia