262 @ 1992 The Japanese Society of Pathology
Case Reports
Disseminated Pneurnocystis Carinii Infection in a Hemophiliac Patient with Acquired Immunodeficiency Syndrome
Torno Waka bayashi', Shinichi Oka2, Kaoru Shimada', Imaharu Nakano3, Takeshi Iwatsubo3, and Shigeo Mori] A case of disseminated Pneumocystis carinii (PC) infection in a 28 year-old Japanese male hemophiliac with acquired immunodeficiency syndrome (AIDS) is reported. The patient had displayed a high fever and diffuse faint interstitial infiltrates on chest X-ray films without dyspnea three months before his death. At that time, no PC was detected after four consecutive induced sputum tests. Serum anti-cytomegalovirus (CMV) IgM was positive by EIA. No treatment for PC and CMV was given at the patient's request. Autopsy findings disclosed disseminated PC infection consisting of granulomas with caseationlike necrosis and frothy exudate in the lungs and disseminated organized calcification in the blood vessels of extrapulmonary organs. PC cysts and/or trophozoites were detected in these lesions. Acta Pathol Jpn 42 : 262266, 1992.
Key words : AIDS, Pneumocystis carinii, Dissemination
It is well known that Pneurnocystis carinii (PC) infection occurs frequently in patients with immunodeficiency and that it is generally confined t o the lungs. However, in rare cases, its spread t o extrapulmonary organs has been described. Until recently such reports have appeared only sporadically (1 -5). Now, however, extrapulmonary dissemination of PC infection is a phenomenon that has been rapidly increasing among AIDS patients (6 14). In Japan, since there have been only a few such case reports (9), this disease may be overlooked because of its unfamiliarity, and therefore in the present report we describe a case of PC dissemination in a patient with -
-~ ~
_
_
_
_
Received July 31, 1991. Accepted for publication December 9, 1991. Departments of lPathology and 21nfectiousDisease, the Institute of Medical Science, the University of Tokyo, Tokyo. 3Department of Neuropathology, the Institute of Brain Research, the University of Tokyo, Tokyo. Mailing address: Torno Wakabayashi, The Central Clinical Laboratory, the Institute of Medical Science, the University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108, Japan.
AIDS.
CASEREPORT A 2 8 year-old Japanese hemophiliac male visited our hospital in May 1988. Laboratory examinations revealed positivity for HIV-1 antibody by EIA, and this was confirmed by Westernblotting. CD4-positive lymphocyte count was 280/mm3 and serum p 2 4 antigen was detected. Physical examination revealed oral candidiasis. The patient had suffered from meningitis two years before, and positivity for HIV-1 antibody had been pointed out on that occasion. He had a history of epilepsy and had received anticonvulsant drugs for over 2 0 years. On December 20, 1989, the patient suffered sudden onset of paraplegia in the lower extremities and was confined t o bed thereafter. On January 23, 1990, he was hospitalized for grand ma1 seizure without respiratory complaints. The CD4-positive lymphocyte count was 8/mm3. On February 28, 1990, the patient's temperature rose t o 39"C, but there was no dyspnea or rales in the chest. However, chest X-ray films showed very faint diffuse interstitial infiltrates, and arterial blood oxygen pressure on room air was 62.9 m m H g with an alveolar-arterial gradient of 43.2 mmHg. No PC cysts were detected after four consecutive induced sputum tests. Serum anti-CMV IgM antibody was 3.60 by EIA. Serum IgG, A, and M levels were 3,722, 1,093, and 2 6 2 mg/dl, respectively. Since the patient refused further medication, he was not given any drugs, including those against PC. Multiple white spots with hemorrhage appeared o n the bilateral retinae on May 7. His general condition deteriorated thereafter, and he died o n May 25, 1990. He had never suffered dyspnea throughout the entire course of his illness. An autopsy was performed. Removed organs were processed routinely, and
Acta Pathologica Japonica 42 (4): 1992
paraffin sections were deparaffinized, stained with hematoxylin and eosin (HE), periodic acid-methenamine silver (PAM), Grocott methenamine silver (Grocott), periodic acid-Schiff (PAS), and toluidine blue 0. In addition, depa raffinized sections were immunosta ined with Dakopneumocystis monoclonal antibody (Dakopatts, Glostrup, Denmark) by the three-stage immunoperoxidase technique using labeled avidin-biotin (LAB, Dakopatts).
PATHOLOGICAL FINDINGS The most remarkable and peculiar findings were the formation of granulomas resembling tuberculosis in the lungs and disseminated calcification corresponding to the course of blood vessels in extrapulmonary organs. The calcification was organized, lined with endothelium, and anchored to part of the vessel wall. Each calcified mass occupied almost the entire lumen of the vein. Frothy eosinophilic exudate was seen only in the lungs and adrenals. The lungs were consolidated and weighed 330 g (left lobe) and 430 g (right lobe). There was no pleural adhesion, pneumothorax or pleural fluid. Most of the cut surfaces were whitish, but those of the bilateral lower lobes showed dark red mottling. Yellowish dots of calcification were sparsely present in both the whitish and dark red cut surfaces. A cavity measuring about 1 cm in diameter with a draining bronchus was observed in the subpleural region on the mediastinal side of the right lower lobe (Fig. 1). Whitish cut surfaces showed interstitial pneumonia or aspiration pneumonia, whereas in the dark red ones this was intermingled with granulomas measuring 0.5 to 2.0 cm in diameter and/or hemorrhage. In some alveolar lumina, a frothy eosinophilic exudate typical of PC cysts (Fig. 2) was observed. The alveolar septa were thickened by infiltration of plasma cells and lymphocytes. Scattered granulomas (Fig. 3) showed eosinophilic coagulation necrosis with or without calcification in their centers, infiltration of macrophages and neutrophils near the necrotic areas, and proliferation of foamy histiocytes intermingled with plasma cells and lymphocytes at the periphery. Multinucleated giant cells including Langhans-type cells were seen occasionally, but typical epithelioid cells were absent. These granulomas apparently resembled tuberculous granulomas with caseation necrosis, but differed from them in the strict sense as described above, and also because of their negative auramine staining for acid-fast bacilli. In the areas of caseation necrosis in granulomas, massive cysts and trophozoites of PC were observed, and in the frothy eosinophilic exudate in alveolar lumina, many cysts (Fig. 2) were present. In multiple
263
necrotic blood vessels of the large area of caseation necrosis forming a cavity, many PC cysts were revealed by Grocott (Fig. 4) and toluidine blue 0 staining, and many trophozoites were demonstrated by PAS staining and immunostaining. The macrophages infiltrating the cavity wall were shown by immunostaining to phagocytize PC parasites. However, in foamy histiocytes surrounding the cavity, PCs were not detectable. In some granulomas, no necrosis was found, but small numbers of PC parasites were detected by immunostaining, surrounded by fibrous tissue. Small numbers of cytomegalic inclusions were also observed near a granuloma, but they were not found in the cavity wall. The spleen weighed 300 g and showed an increase in consistency. In the cut surfaces, multiple calcifications
Figure 1. The lungs are consolidated with dark red mottling against a whitish background of interstitial pneumonia On the mediastinal side of the right lower lobe, a cavity measuring about 1 cm in diameter is evident (arrow).
Figure2. The frothy exudate in the alveoli is positively immunostained with anti-PC monoclonal antibody.
264
Pneumocystis Carinii Dissemination in AIDS (Wakabayashi et a/.)
Figure 3. A granuloma in the lung. Coagulation necrosis similar to caseation necrosis and proliferation of foamy cells in the surrounding area are observed. Calcification is scattered. A Langhans-type giant cell is present (arrow). HE.
Figure4. A necrotic vessel near the cavity in the right lower lobe is filled with many PC cysts. Grocott staining.
Figure 5. The spleen shows an increase in consistency and exhibits multiple calcification in accordance with the distribution of blood vessels.
Figure 6. A large calcified embolus in the trabecular vein of the spleen. PAS.
Figure 7.
PC cysts are clearly demonstrated by Grocott staining in the embolus shown in Fig. 6.
2 65
Acta Pathologica Japonica 42 (4) : 1992
Figure8. A calcified embolus in a vein of the portal tract in the liver. It is anchored to the venous wall and its surface is covered with endothelium. HE.
-
Figure 9. A lymph node demonstrates marked depletion of lymphocytes and prominent PAS-positive calcification. PAS.
were observed, corresponding to the distribution of blood vessels (Fig. 5). Microscopically, calcification was observed mostly in the lumina of trabecular veins (Fig. 6) and sometimes in the red pulp. In these lesions, PC cysts (Fig. 7) and trophozoites were detected by Grocott and PAS staining, respectively. In the trabecular stroma, small numbers of cysts were detected by immunostaining. The liver weighed 1,200 g and was icteric. In the cut surfaces, a few dots of calcification were seen and tended to become detached easily from the cut surface. Microscopically, small foci of organized calcification were localized in the veins of the portal tract infiltrated by plasma cells and lymphocytes in small numbers (Fig. 8). A few PC cysts were sometimes detected in the calcified foci. In lobules, minute foci of hepatocyte drop-out were scattered, with cellular reaction. In these areas no parasites were found with either of the above staining techniques. In the right kidney (120 g) a relatively large organized calcified mass including parasites was in the renal vein at the hilus. Multiple calcifications were observed also in the bilateral adrenals, various lymph nodes (Figs. 9, 10) and abdominal and pelvic fatty tissues. In these lesions, PC parasites were found in various amounts. In the adrenals, small areas of frothy exudate were seen near sites of calcification. Relatively many cytomegalic inclusions were also found. In the brain (1,340 g), spinal cord, bone marrow, and some other organs, no calcification or lesions suspected to be due to PC were revealed. The eyes were not examined. Lymph nodes showed depletion of lymphocytes and fibrosis as well as foci of PC infection. The bone marrow demonstrated granulocytic hyperplasia. The direct cause of the patient’s death was extensive subarachnoidal bleeding of the basal brain and parenchymal bleeding in the frontal lobes. The basic pathological change in the central nervous system was AIDS encephalopathy and myelopathy. In addition, mild CMV infection was superimposed.
DISCUSSION
Figure 10. Magnified view of part of Fig. 9. Strongly PASpositive entangled bodies a re PC t ro phozoites (arrow S), and shadowy area represents PC cysts (arrowheads). PAS.
The most prominent pathological features in the present case were granuloma formation in the lungs and dissemination of minute calcified foci in various organs. A frothy exudate typical of PC infection was observed in the lungs and adrenals. The granulomas in this case apparently resembled tuberculous ones (4, 15, 16) because they showed coagulation necrosis, but no typical epithelioid cells were observed. Such granuloma forma-
266
Pneurnocystis Carinii Dissemination in AIDS (Wakabayashi et a/.)
tion in the lungs suggests that long-standing PC infection must have been present before it became widespread. Disseminated calcified foci tended to occur in the veins. Within these foci, PC parasites were frequently, but not always detected, and therefore these were thought to be parasitic emboli. It is speculated that the subarachnoidal and cerebral bleeding that caused the patient's death occurred before the PC parasites in the emboli had invaded the surrounding tissues through the veins. The last event must have occurred accidentally very soon after these emboli had formed in various organs. In cases where PC dissemination has been fatal, extensive frothy exudate o r necrosis is frequently observed in many organs (2, 3, 5--7, 9, 10, 13, 14). It can be inferred in the present case that because the portal vein contained a decreased number of parasites after many of them had been trapped by the spleen, the number of calcified foci in the liver was much lower than that in the spleen. Multiple minute foci of hepatocyte drop-out with cellular reaction might have represented traces of a host reaction with the parasites. Dissemination of calcified foci is occasionally observed in systemic P C infection (4, 7, 9). Some investigators have speculated that the recent rapid increase of extrapulmonary dissemination of PC infection in AIDS patients may be due to prophylactic inhalation of the anti-PC drug pentamidine (10-1 2, 14). However, the present patient had not taken this drug. Hypogammaglobulinemia or hypoproteinemia is thought t o provide conditions suitable f o r PC dissemination (2, 5, 9, 10). The levels of immunoglobulins in this patient were rather high (IgG : 3,722 mg/dl, IgA : 1,093 mg/dl, IgM : 262 mg/ dl) three months before his death, when the initial pulmonary infiltrates appeared o n chest X-ray films, but thereafter they were unclear because he refused medication and examination. Finally, in the calcified foci, PC cysts were clearly demonstrated by Grocott staining, and PC trophozoites by PAS and immunostaining. Thus it is recommended that various staining techniques should be used f o r detection of PC cysts and/or trophozoites. Acknowledgements ; The authors are grateful to Dr. T. Furuta, Department of Parasitology, Institute of Medical Science, University of Tokyo, for valuable discussions, and to Mr. H. Onoda and Miss Y. Kuroda for excellent technical assistance.
prematures. 2.
3. 4. 5. 6.
7.
8.
9.
10.
11.
12.
13. 14.
15. 16.
REFERENCES 1. Zandanell E. Pneumocystis findings outside the lungs in interstitial plasma cell pneumonia of the infants and
Zentralbl Allg Pathol 92 : 74-80, 1954
(in German).
Jarnum S, Rasmussen EF, Ohlsen AS, and Sorenson AWS. Generalized Pneumocystis carinii infection with severe idiopathic hypoproteinemia. Ann Intern Med 68: 138-145, 1968. Awen CF and Baltzan MA. Systemic dissemination of Pneumocystis carinii pneumonia. Can Med Assoc J 1 0 4 : 809-812, 1971. LeGolvan DP, Heidelberger KP, and Arbor A. Disseminated granulomatous Pneumocystis carinii pneumonia. Arch Pathol 95: 344 348, 1973. Rahimi SA. Disseminated Pneumocystis carinii in thymic alymphoplasia. Arch Pathol 9 7 : 162-165, 1974. Grimes MM, LaPook JD, Bar MH, Wasserman HS, and Dwork A. Disseminated Pneumocystis carinii infection in a patient with acquired immunodeficiency syndrome. Hum Pathol 18: 307-308, 1987. Carter TR, Cooper PH, Petri WA, et a/. Pneumocystis carinii infection of the small intestine in a patient with acquired immune deficiency syndrome. Am J Clin Pathol 89: 679-683, 1987. Gherman CR, Ward RR, and Bassis ML. Pneumocystis carinii otitis media and mastoiditis as the initial manifestation of the acquired immunodeficiency syndrome. Am J Med 8 5 : 250-252, 1988. Matsuda S, Urata Y, Shiota T, et a / . Disseminated infection of Pneumocystis carinii in a patient with the acquired immunodeficiency syndrome. Virchows Arch [A] 414: 523-527, 1989. Poblete RB, Rodriguez K, Foust RT, Reddy KR, and Saldana MJ. Pneumocystis carinii hepatitis in the acquired immunodeficiency syndrome. Ann Intern Med 110: 737-738, 1989. Gary N, Murphy RL, Finn WG, and Timins M. Extrapulmonary Pneumocystis carinii in patients receiving aerosolized pentamidine. Lancet 336: 229, 1990. Michel D, Guidet B, Lebas J, and East Parisian CLSIH Group. Clinical data of disseminated Pneumocystis carinii infection (D.P.C.I.) in 6 AIDS patients receiving secondary prophylaxis with aerosolized penta midine (AP). Lancet 336 : 228, 1990. Mayo E, Vidal F, Alvira R, Gonzalez J, and Richart C. Cerebral Pneumocystis carinii infection. Lancet 336 : 1592, 1990. Dembinski AS, Smith DM, Goldsmith JC, and Woods GL. Widespread dissemination of Pneumocystis carmii infection in a patient with acquired immune deficiency syndrome receiving long-term treatment with aerosolized pentamidine. Am J Clin Pathol 95: 96-100, 1991. Cupples JB, Blackie SP, and Road JD. Granulomatous Pneumocystis carinii pneumonia mimicking tuberculosis. Arch Pathol Lab Med 1 1 3 : 1281-1284, 1989. Weber WR, Askin FB, and Dehner LP. Lung biopsy in Pneumocysfis carinii pneumonia. A histopathologic study of typical and atypical features. Am J Clin Pathol 6 7 : 11-19, 1977.
Case Reports
Disseminated Pneurnocystis Carinii Infection in a Hemophiliac Patient with Acquired Immunodeficiency Syndrome
Torno Waka bayashi', Shinichi Oka2, Kaoru Shimada', Imaharu Nakano3, Takeshi Iwatsubo3, and Shigeo Mori] A case of disseminated Pneumocystis carinii (PC) infection in a 28 year-old Japanese male hemophiliac with acquired immunodeficiency syndrome (AIDS) is reported. The patient had displayed a high fever and diffuse faint interstitial infiltrates on chest X-ray films without dyspnea three months before his death. At that time, no PC was detected after four consecutive induced sputum tests. Serum anti-cytomegalovirus (CMV) IgM was positive by EIA. No treatment for PC and CMV was given at the patient's request. Autopsy findings disclosed disseminated PC infection consisting of granulomas with caseationlike necrosis and frothy exudate in the lungs and disseminated organized calcification in the blood vessels of extrapulmonary organs. PC cysts and/or trophozoites were detected in these lesions. Acta Pathol Jpn 42 : 262266, 1992.
Key words : AIDS, Pneumocystis carinii, Dissemination
It is well known that Pneurnocystis carinii (PC) infection occurs frequently in patients with immunodeficiency and that it is generally confined t o the lungs. However, in rare cases, its spread t o extrapulmonary organs has been described. Until recently such reports have appeared only sporadically (1 -5). Now, however, extrapulmonary dissemination of PC infection is a phenomenon that has been rapidly increasing among AIDS patients (6 14). In Japan, since there have been only a few such case reports (9), this disease may be overlooked because of its unfamiliarity, and therefore in the present report we describe a case of PC dissemination in a patient with -
-~ ~
_
_
_
_
Received July 31, 1991. Accepted for publication December 9, 1991. Departments of lPathology and 21nfectiousDisease, the Institute of Medical Science, the University of Tokyo, Tokyo. 3Department of Neuropathology, the Institute of Brain Research, the University of Tokyo, Tokyo. Mailing address: Torno Wakabayashi, The Central Clinical Laboratory, the Institute of Medical Science, the University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108, Japan.
AIDS.
CASEREPORT A 2 8 year-old Japanese hemophiliac male visited our hospital in May 1988. Laboratory examinations revealed positivity for HIV-1 antibody by EIA, and this was confirmed by Westernblotting. CD4-positive lymphocyte count was 280/mm3 and serum p 2 4 antigen was detected. Physical examination revealed oral candidiasis. The patient had suffered from meningitis two years before, and positivity for HIV-1 antibody had been pointed out on that occasion. He had a history of epilepsy and had received anticonvulsant drugs for over 2 0 years. On December 20, 1989, the patient suffered sudden onset of paraplegia in the lower extremities and was confined t o bed thereafter. On January 23, 1990, he was hospitalized for grand ma1 seizure without respiratory complaints. The CD4-positive lymphocyte count was 8/mm3. On February 28, 1990, the patient's temperature rose t o 39"C, but there was no dyspnea or rales in the chest. However, chest X-ray films showed very faint diffuse interstitial infiltrates, and arterial blood oxygen pressure on room air was 62.9 m m H g with an alveolar-arterial gradient of 43.2 mmHg. No PC cysts were detected after four consecutive induced sputum tests. Serum anti-CMV IgM antibody was 3.60 by EIA. Serum IgG, A, and M levels were 3,722, 1,093, and 2 6 2 mg/dl, respectively. Since the patient refused further medication, he was not given any drugs, including those against PC. Multiple white spots with hemorrhage appeared o n the bilateral retinae on May 7. His general condition deteriorated thereafter, and he died o n May 25, 1990. He had never suffered dyspnea throughout the entire course of his illness. An autopsy was performed. Removed organs were processed routinely, and
Acta Pathologica Japonica 42 (4): 1992
paraffin sections were deparaffinized, stained with hematoxylin and eosin (HE), periodic acid-methenamine silver (PAM), Grocott methenamine silver (Grocott), periodic acid-Schiff (PAS), and toluidine blue 0. In addition, depa raffinized sections were immunosta ined with Dakopneumocystis monoclonal antibody (Dakopatts, Glostrup, Denmark) by the three-stage immunoperoxidase technique using labeled avidin-biotin (LAB, Dakopatts).
PATHOLOGICAL FINDINGS The most remarkable and peculiar findings were the formation of granulomas resembling tuberculosis in the lungs and disseminated calcification corresponding to the course of blood vessels in extrapulmonary organs. The calcification was organized, lined with endothelium, and anchored to part of the vessel wall. Each calcified mass occupied almost the entire lumen of the vein. Frothy eosinophilic exudate was seen only in the lungs and adrenals. The lungs were consolidated and weighed 330 g (left lobe) and 430 g (right lobe). There was no pleural adhesion, pneumothorax or pleural fluid. Most of the cut surfaces were whitish, but those of the bilateral lower lobes showed dark red mottling. Yellowish dots of calcification were sparsely present in both the whitish and dark red cut surfaces. A cavity measuring about 1 cm in diameter with a draining bronchus was observed in the subpleural region on the mediastinal side of the right lower lobe (Fig. 1). Whitish cut surfaces showed interstitial pneumonia or aspiration pneumonia, whereas in the dark red ones this was intermingled with granulomas measuring 0.5 to 2.0 cm in diameter and/or hemorrhage. In some alveolar lumina, a frothy eosinophilic exudate typical of PC cysts (Fig. 2) was observed. The alveolar septa were thickened by infiltration of plasma cells and lymphocytes. Scattered granulomas (Fig. 3) showed eosinophilic coagulation necrosis with or without calcification in their centers, infiltration of macrophages and neutrophils near the necrotic areas, and proliferation of foamy histiocytes intermingled with plasma cells and lymphocytes at the periphery. Multinucleated giant cells including Langhans-type cells were seen occasionally, but typical epithelioid cells were absent. These granulomas apparently resembled tuberculous granulomas with caseation necrosis, but differed from them in the strict sense as described above, and also because of their negative auramine staining for acid-fast bacilli. In the areas of caseation necrosis in granulomas, massive cysts and trophozoites of PC were observed, and in the frothy eosinophilic exudate in alveolar lumina, many cysts (Fig. 2) were present. In multiple
263
necrotic blood vessels of the large area of caseation necrosis forming a cavity, many PC cysts were revealed by Grocott (Fig. 4) and toluidine blue 0 staining, and many trophozoites were demonstrated by PAS staining and immunostaining. The macrophages infiltrating the cavity wall were shown by immunostaining to phagocytize PC parasites. However, in foamy histiocytes surrounding the cavity, PCs were not detectable. In some granulomas, no necrosis was found, but small numbers of PC parasites were detected by immunostaining, surrounded by fibrous tissue. Small numbers of cytomegalic inclusions were also observed near a granuloma, but they were not found in the cavity wall. The spleen weighed 300 g and showed an increase in consistency. In the cut surfaces, multiple calcifications
Figure 1. The lungs are consolidated with dark red mottling against a whitish background of interstitial pneumonia On the mediastinal side of the right lower lobe, a cavity measuring about 1 cm in diameter is evident (arrow).
Figure2. The frothy exudate in the alveoli is positively immunostained with anti-PC monoclonal antibody.
264
Pneumocystis Carinii Dissemination in AIDS (Wakabayashi et a/.)
Figure 3. A granuloma in the lung. Coagulation necrosis similar to caseation necrosis and proliferation of foamy cells in the surrounding area are observed. Calcification is scattered. A Langhans-type giant cell is present (arrow). HE.
Figure4. A necrotic vessel near the cavity in the right lower lobe is filled with many PC cysts. Grocott staining.
Figure 5. The spleen shows an increase in consistency and exhibits multiple calcification in accordance with the distribution of blood vessels.
Figure 6. A large calcified embolus in the trabecular vein of the spleen. PAS.
Figure 7.
PC cysts are clearly demonstrated by Grocott staining in the embolus shown in Fig. 6.
2 65
Acta Pathologica Japonica 42 (4) : 1992
Figure8. A calcified embolus in a vein of the portal tract in the liver. It is anchored to the venous wall and its surface is covered with endothelium. HE.
-
Figure 9. A lymph node demonstrates marked depletion of lymphocytes and prominent PAS-positive calcification. PAS.
were observed, corresponding to the distribution of blood vessels (Fig. 5). Microscopically, calcification was observed mostly in the lumina of trabecular veins (Fig. 6) and sometimes in the red pulp. In these lesions, PC cysts (Fig. 7) and trophozoites were detected by Grocott and PAS staining, respectively. In the trabecular stroma, small numbers of cysts were detected by immunostaining. The liver weighed 1,200 g and was icteric. In the cut surfaces, a few dots of calcification were seen and tended to become detached easily from the cut surface. Microscopically, small foci of organized calcification were localized in the veins of the portal tract infiltrated by plasma cells and lymphocytes in small numbers (Fig. 8). A few PC cysts were sometimes detected in the calcified foci. In lobules, minute foci of hepatocyte drop-out were scattered, with cellular reaction. In these areas no parasites were found with either of the above staining techniques. In the right kidney (120 g) a relatively large organized calcified mass including parasites was in the renal vein at the hilus. Multiple calcifications were observed also in the bilateral adrenals, various lymph nodes (Figs. 9, 10) and abdominal and pelvic fatty tissues. In these lesions, PC parasites were found in various amounts. In the adrenals, small areas of frothy exudate were seen near sites of calcification. Relatively many cytomegalic inclusions were also found. In the brain (1,340 g), spinal cord, bone marrow, and some other organs, no calcification or lesions suspected to be due to PC were revealed. The eyes were not examined. Lymph nodes showed depletion of lymphocytes and fibrosis as well as foci of PC infection. The bone marrow demonstrated granulocytic hyperplasia. The direct cause of the patient’s death was extensive subarachnoidal bleeding of the basal brain and parenchymal bleeding in the frontal lobes. The basic pathological change in the central nervous system was AIDS encephalopathy and myelopathy. In addition, mild CMV infection was superimposed.
DISCUSSION
Figure 10. Magnified view of part of Fig. 9. Strongly PASpositive entangled bodies a re PC t ro phozoites (arrow S), and shadowy area represents PC cysts (arrowheads). PAS.
The most prominent pathological features in the present case were granuloma formation in the lungs and dissemination of minute calcified foci in various organs. A frothy exudate typical of PC infection was observed in the lungs and adrenals. The granulomas in this case apparently resembled tuberculous ones (4, 15, 16) because they showed coagulation necrosis, but no typical epithelioid cells were observed. Such granuloma forma-
266
Pneurnocystis Carinii Dissemination in AIDS (Wakabayashi et a/.)
tion in the lungs suggests that long-standing PC infection must have been present before it became widespread. Disseminated calcified foci tended to occur in the veins. Within these foci, PC parasites were frequently, but not always detected, and therefore these were thought to be parasitic emboli. It is speculated that the subarachnoidal and cerebral bleeding that caused the patient's death occurred before the PC parasites in the emboli had invaded the surrounding tissues through the veins. The last event must have occurred accidentally very soon after these emboli had formed in various organs. In cases where PC dissemination has been fatal, extensive frothy exudate o r necrosis is frequently observed in many organs (2, 3, 5--7, 9, 10, 13, 14). It can be inferred in the present case that because the portal vein contained a decreased number of parasites after many of them had been trapped by the spleen, the number of calcified foci in the liver was much lower than that in the spleen. Multiple minute foci of hepatocyte drop-out with cellular reaction might have represented traces of a host reaction with the parasites. Dissemination of calcified foci is occasionally observed in systemic P C infection (4, 7, 9). Some investigators have speculated that the recent rapid increase of extrapulmonary dissemination of PC infection in AIDS patients may be due to prophylactic inhalation of the anti-PC drug pentamidine (10-1 2, 14). However, the present patient had not taken this drug. Hypogammaglobulinemia or hypoproteinemia is thought t o provide conditions suitable f o r PC dissemination (2, 5, 9, 10). The levels of immunoglobulins in this patient were rather high (IgG : 3,722 mg/dl, IgA : 1,093 mg/dl, IgM : 262 mg/ dl) three months before his death, when the initial pulmonary infiltrates appeared o n chest X-ray films, but thereafter they were unclear because he refused medication and examination. Finally, in the calcified foci, PC cysts were clearly demonstrated by Grocott staining, and PC trophozoites by PAS and immunostaining. Thus it is recommended that various staining techniques should be used f o r detection of PC cysts and/or trophozoites. Acknowledgements ; The authors are grateful to Dr. T. Furuta, Department of Parasitology, Institute of Medical Science, University of Tokyo, for valuable discussions, and to Mr. H. Onoda and Miss Y. Kuroda for excellent technical assistance.
prematures. 2.
3. 4. 5. 6.
7.
8.
9.
10.
11.
12.
13. 14.
15. 16.
REFERENCES 1. Zandanell E. Pneumocystis findings outside the lungs in interstitial plasma cell pneumonia of the infants and
Zentralbl Allg Pathol 92 : 74-80, 1954
(in German).
Jarnum S, Rasmussen EF, Ohlsen AS, and Sorenson AWS. Generalized Pneumocystis carinii infection with severe idiopathic hypoproteinemia. Ann Intern Med 68: 138-145, 1968. Awen CF and Baltzan MA. Systemic dissemination of Pneumocystis carinii pneumonia. Can Med Assoc J 1 0 4 : 809-812, 1971. LeGolvan DP, Heidelberger KP, and Arbor A. Disseminated granulomatous Pneumocystis carinii pneumonia. Arch Pathol 95: 344 348, 1973. Rahimi SA. Disseminated Pneumocystis carinii in thymic alymphoplasia. Arch Pathol 9 7 : 162-165, 1974. Grimes MM, LaPook JD, Bar MH, Wasserman HS, and Dwork A. Disseminated Pneumocystis carinii infection in a patient with acquired immunodeficiency syndrome. Hum Pathol 18: 307-308, 1987. Carter TR, Cooper PH, Petri WA, et a/. Pneumocystis carinii infection of the small intestine in a patient with acquired immune deficiency syndrome. Am J Clin Pathol 89: 679-683, 1987. Gherman CR, Ward RR, and Bassis ML. Pneumocystis carinii otitis media and mastoiditis as the initial manifestation of the acquired immunodeficiency syndrome. Am J Med 8 5 : 250-252, 1988. Matsuda S, Urata Y, Shiota T, et a / . Disseminated infection of Pneumocystis carinii in a patient with the acquired immunodeficiency syndrome. Virchows Arch [A] 414: 523-527, 1989. Poblete RB, Rodriguez K, Foust RT, Reddy KR, and Saldana MJ. Pneumocystis carinii hepatitis in the acquired immunodeficiency syndrome. Ann Intern Med 110: 737-738, 1989. Gary N, Murphy RL, Finn WG, and Timins M. Extrapulmonary Pneumocystis carinii in patients receiving aerosolized pentamidine. Lancet 336: 229, 1990. Michel D, Guidet B, Lebas J, and East Parisian CLSIH Group. Clinical data of disseminated Pneumocystis carinii infection (D.P.C.I.) in 6 AIDS patients receiving secondary prophylaxis with aerosolized penta midine (AP). Lancet 336 : 228, 1990. Mayo E, Vidal F, Alvira R, Gonzalez J, and Richart C. Cerebral Pneumocystis carinii infection. Lancet 336 : 1592, 1990. Dembinski AS, Smith DM, Goldsmith JC, and Woods GL. Widespread dissemination of Pneumocystis carmii infection in a patient with acquired immune deficiency syndrome receiving long-term treatment with aerosolized pentamidine. Am J Clin Pathol 95: 96-100, 1991. Cupples JB, Blackie SP, and Road JD. Granulomatous Pneumocystis carinii pneumonia mimicking tuberculosis. Arch Pathol Lab Med 1 1 3 : 1281-1284, 1989. Weber WR, Askin FB, and Dehner LP. Lung biopsy in Pneumocysfis carinii pneumonia. A histopathologic study of typical and atypical features. Am J Clin Pathol 6 7 : 11-19, 1977.
