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MARTIN-REAY, SHATTUCK, AND GUTHRIE 489 Psammomatous Melanotic Schwannoma 19. Carney JA, Gordon H, Carpenter PC, Shenoy BV, Go VLW. The complex of myxomas, spotty pigmentation, and endocrine overactivity. Medicine (Baltimore) 1985;64:270-283. 20. Carney JA, Headington JT, Su WPD. Cutaneous myxomas. A major component of the complex of myxomas, spotty pigmentation and endocrine overactivity. Arch Dermatol 1986;122:790-798. 21. Cook CA, Lund BA, Carney JA. Mucocutaneous pigmented spots and oral myxomas: the oral manifestations of the complex of myxomas, spotty pigmentation and endocrine overactivity. Oral Surg Oral Med Oral Pathol 1987;63:175-183. 22. Schweizer-Cagianut M, Salomon F, Hedinger CE. Primary adre- nocortical nodular dysplasia with Cushing's syndrome and cardiac myxomas. A peculiar familial disease. Virchows Arch [A] 1982;397:183-192. 23. Shennoy BV, Carpenter PC, Carney JA. Bilateral primary pigmented nodular adrenocortical disease. Rare cause of the Cushing's syndrome. Am J Surg Pathol 1984;8:335-344. 24. Vatterott PJ, Seward JB, Vidaillet JH, Su WPD, Oftedahl GL. Syndrome cardiac myxoma: more than just a sporadic event. Am Heart J 1987;114:886-889. 25. Proppe KH, Scully RE. Large-cell calcifying Sertoli cell tumor of the testis. Am J Clin Pathol 1980;74:607-619. Pneumocystis carinii Infection Presenting as Necrotizing Thyroiditis and Hypothyroidism MARGARET V. RAGNI, M.D., ANDREW DEKKER, M.D., FREDERICK R. D E R U B E R T I S , M.D., CHARLES G. WATSON, M.D., M. LEON SKOLNICK, M.D., SUSAN D. GOOLD, M.D., MICHAEL W. FINIKIOTIS, M.D., SALIL DOSHI, M.D., AND DELYNNE J. MYERS, M.D. Extrapulmonary Pneumocystis infection has been increasingly reported in patients with acquired immune deficiency syndrome (AIDS), in particular, recently in association with the increasing use of aerosolized pentamidine. This report describes the unusual presentation of extrapulmonary Pneumocystis infection as a thyroid neck mass and clinical hypothyroidism in a 37-year-old man with hemophilia and AIDS. This case differs from the previously reported single case of isolated thyroid pneumocystosis in the presence of a rapidly enlarging neck mass, lack of previous Pneumocystis, and prior prophylaxis with aerosolized pentamidine. The pathologic and electron microscopic description of the peculiar flocculent necrotic thyroid material is contrasted with typical pulmonary alveolar findings in Pneumocystis pneumonia (PCP), the differential diagnoses of a rapidly expanding neck mass, and diagnostic difficulties of hypothyroidism in patients with AIDS are discussed. Finally, it is emphasized that use of aerosolized pentamidine, although successful for prevention of pulmonary PCP, may be insufficient to prevent extrapulmonary infection. (Key words: Pneumocystis carinii pneumonia |PCPJ; Acquired immune deficiency syndrome (AIDS); Extrapulmonary pneumocystosis; Thyroid mass) Am J Clin Pathol 199I;95: 489-493 Despite advances in treatment and prophylaxis, Pneumocystis carinii pneumonia (PCP) continues to be the most c o m m o n opportunistic infection reported in patients with acquired immune deficiency syndrome (AIDS), with more than 60% of patients with AIDS presenting with PCP and another 20% having PCP as a later diagnosis.1,2 Although PCP is regarded as a primary pulmonary pathogen, there have been increasing reports of extrapulmonary Pneumocystis infection.3"5 These may relate, in part, to the recent introduction of aerosolized pentamidine, 6 which, with only minimal systemic absorption,7 promotes eradication of pulmonary Pneumocystis while allowing unchecked development of nonpulmonary Pneumocystis. Recently we cared for a patient with hemophilia and AIDS who presented with an acute diffuse goiter, hypothyroidism, and P. carinii of the thyroid. REPORT OF A CASE From the Departments ofMedicine. Radiology, Surgery, and Pathology, University of Pittsburgh School ofMedicine, and the Hemophilia Center A 37-year-old man with severe hemophilia A (< 0.01 U/mL Factor of Western Pennsylvania, Pittsburgh, Pennsylvania. VIII:C) and AIDS presented in July 1989 with a painful right neck mass and transient dysarthria. There had been no trauma. Ultrasound revealed Received March 8, 1990; received revised manuscript and accepted the mass to be an enlarged right lobe of the thyroid, with echogenic areas for publication April 5, 1990. consistent with calcification and suggestive of hematoma. The left lobe Address reprint requests to Dr. Ragni: Hemophilia Center of Western appeared normal. Treatment with Factor VIII concentrate therapy rePennsylvania, 812 Fifth Avenue, Pittsburgh, Pennsylvania 15219. Vol. 95 • No. 4 490 ANATOMIC PATHOLOGY Single Case Reports FIG. 1 (upper). Transverse ultrasound scan through right lobe of thyroid, 10/89. Hyperechoic regions (H) and regions of acoustic (S) suggest presence of calcifications. A, carotid artery; V, jugular vein; L, laryngeal cartilage. FIG. 2 (lower). Transverse postcontrast computerized tomographic scan of entire thyroid confirms presence of calcification (C) in both lobes, more so in the left lobe. A, carotid artery; V, jugular vein; L, laryngeal cartilage. A.J.C.P. • April 1991 RAGNI ET AL. Pneumocystis Infection of the Thyroid suited in cessation of pain and minimal decrease in size of the neck mass. Neurologic examination, lumbar puncture, and computerized tomographic (CT) scan of the head were unremarkable. Thyroid function tests revealed T4 of 131 nmol/L (normal 63-130), T3 uptake of 0.88 (normal, 0.8-1.2), free thyroxine index of 9.0 (normal, 5.0-12.0), and thyroidstimulating hormone (TSH) levels of 2.8 mU/L (normal 0.5-10.0). In October 1989, at a routine semiyearly examination, diffuse massive painless enlargement of the thyroid gland was observed, unrecognized by the patient or his wife, which was accompanied by a 12-pound weight loss in four weeks, anorexia, irritability, and fatigue. There were no sweats, fevers, odynophagia, hoarseness, or precedent trauma. A 90-pound weight loss had occurred over the preceding year, associated with intermittent nonwatery, culture-negative diarrhea. A diagnosis of AIDS was made in May 1989, when the patient presented with Candida esophagitis. Medications included zidovudine (AZT) I g daily for the previous 15 months, ketoconazole 100 mg daily for the previous 5 months, and aerosolized pentamidine 300 mg monthly (via Respirgard II®, Marquest Medical Products, Inc., Englewood, CO) for the previous 7 months. Physical examination revealed a temperature of 36.9 °C, blood pressure 104/60 mmHg, pulse 80 per minute. The skin was dry and doughy, with significant wasting. Speech and mentation were slowed, and deep tendon reflexes could not be elicited. The thyroid gland was firm, nontender, and diffusely enlarged, with the right lobe measuring 9 X 4 cm and the left lobe measuring 8 X 3 cm. Lymph nodes in the posterior cervical and anterior cervical chain were enlarged (0.5 — 1.5 cm) bilaterally. Hepatosplenomegaly was present. Ultrasonography revealed a diffusely 491 enlarged gland, right greater than left, with echogenic regions and shadowing suggestive of calcifications bilaterally (Fig. 1). Computed tomography scan confirmed thesefindings:the right lobe measured 9 X 4 X 3 cm and the left lobe 8 X 3 X 3 cm with bilateral calcification (Fig. 2). Thyroid function tests revealed T4 of 49 nmol/L, T3 uptake of 0.64 (0.81.2) and a TSH level of 33 mU/L. Antithyroglobulin and antimicrosomal antibodies were negative at less than 100. The thyroid-binding globulin level was 60 nmol/L (15-31). Afine-needlebiopsy and tru-cut biopsy of the right lobe of the thyroid gland, performed under coverage of Factor VIII concentrate, revealed significantly abnormal thyroid tissue of a pale pink color. Cytologic results revealed macrophages but no malignant cells. Hematoxylin and eosin staining revealed extensive necrosis with a peculiar flocculent appearance (Fig. 3); in addition, there was granulomatous inflammation with extensive destruction and gross distortion of the thyroid architecture. Only occasional thyroid follicles were present, confirmed by immunoperoxidase keratin (Fig. 3, inset) and thyroglobulin staining. Extensive calcification was present throughout the tissue sections (not shown). P. carinii organisms were detected on Grocott staining of both the tissue section (Fig. 4) and the decolorized glass slides originally prepared for cytologic examination and were confirmed by electron microscopic examination of the deparaffinized tru-cut tissue block (Fig. 5). Thefindingsof pulmonary examination, chest roentgenogram, gallium scan, and pulmonary function tests were normal and pulse oximetry was 96%. Abdominal CT scan revealed hepatosplenomegaly with no focal defects and multiple, bilateral, small renal cortical calcifications. The adrenals appeared normal, with no calcifications. Skin testing re- ^ . w • # * * FIG. 3 (left). Granulomatous inflammation andflocculentmaterial seen in a low-power photomicrograph. Thyroid follicle at arrow. Inset. Thyroid follicle as shown by immunoperoxidase keratin stain. Hematoxylin and eosin (XI25). Inset (X312). FIG. 4 (right). Typical Pneumocystis carinii organisms demonstrated. Grocott (X 1,250). Vol. 95 • No. 4 492 ANATOMIC PATHOLOGY Single Case Reports FIG. 5. Electron micrograph of Pneumocystis carinii. Lead citrate and uranyl acetate (X22.700). vealed reactivity to mumps and Trichophyton antigens but no reactivity with purified protein derivative (PPD). The patient was treated with a three-week course of intravenous pentamidine at 4 mg/kg, with gradual shrinkage of the gland and cessation of weight loss. Thyroid replacement was begun with synthetic T4 (Synthroid®; sodium levothyroxine. Flint Laboratories, Deerfield, IL), 75 fig daily. The patient is currently receiving prophylaxis with aerosolized pentamidine and oral Bactrim® (trimethoprim-sulfamethoxazole; Roche Laboratories, Nutley, NJ) and continues on maintenance thyroid replacement. DISCUSSION With the high frequency of P. carinii pneumonia in patients with AIDS and the increasing use of recently approved aerosolized pentamidine prophylaxis, it is not surprising that extrapulmonary Pneumocystis infection has been recognized in patients with AIDS more frequently in the past several years.3"5 Although the thyroid gland has been an involved site in a number of disseminated cases, there has been only one previous case of isolated Pneumocystis infection of the thyroid.8 In contrast to that patient, the hemophiliac reported here had no previous pulmonary symptoms, had been receiving chronic monthly aerosolized pentamidine prophylaxis, and presented with diffuse goiter and hypothyroidism. Given the nonspecific symptoms typical of patients with AIDS, such as weight loss, intermittent diarrhea, mental slowing, fatigue, and depression, a clinical diagnosis of hypothyroidism in a patient with AIDS may be difficult to make. Further, hypothyroidism is uncommon in patients with AIDS because most such patients have normal thyroid function,9 or occasionally a low T 3 level, which may ac- company a severe infection, the so-called "euthyroid sick syndrome." Moreover, in the setting of the severe immunosuppression associated with AIDS and a rapidly growing neck mass, thyroid lymphoma is a more likely diagnosis,10 especially because lymphomas in human immunodeficiency virus- (HIV) positive hemophiliacs have previously presented as "hematomas" in unusual sites." However, the absence of malignant cells on biopsy specimens and the clinical response to pentamidine and thyroid hormone (T4) exclude the possibility of thyroid lymphoma or other malignancy in this patient. Two clues to the pathologist for the proper recognition of the disease processes are12 the peculiar flocculent nature of the necrotic material, not dissimilar to that seen in the alveoli of lungs of patients infected with Pneumocystis, and 5 the granulomatous inflammatory infiltrate observed in the tissue section, and recently emphasized in PCP. 13 Further, although electron microscopic examination is not required for the diagnosis of P. carinii infection, when it is performed, as in this case, it confirms the typical morphologic characteristics of the organism,12 specifically demonstrating the presence of intact cysts and intracystic bodies. Because the latter are eradicated with systemic pentamidine therapy,12 their presence confirms the clinical absence of any systemic effect of aerosolized pentamidine in this patient. The importance of this case, aside from the recognition that extrapulmonary Pneumocystis infection can present as thyroiditis with hypothyroidism, is the growing recognition of the increasing frequency of extrapulmonary AJ.C.P. • April 1991 RAGNI ET AL. 493 Pneumocystis Infection of the Thyroid Pneumocystis in patients with AIDS. This observation suggests that aerosolized pentamidine should be recommended as only part of an effective prophylaxis regimen to prevent Pneumocystis infection in such patients. The combination of intermittent oral trimethoprim-sulfamethoxazole (Bactrim) or intermittent intravenous pentamidine or Bactrim, for example, with aerosolized pentamidine might be considered; unfortunately, the minimal effective dose of such drugs, when used in combination, is not known. In summary, this case illustrates three major points12: extrapulmonary Pneumocystis infection may present as thyroiditis with hypothyroidism5; "hematomas" in unusual sites in HIV-infected hemophiliacs may represent opportunistic infection; and1 aerosolized pentamidine prophylaxis alone may be insufficient to prevent extrapulmonary Pneumocystis infection. Acknowledgments. The authors acknowledge Dr. Julio A. Martinez for performing electron microscopic studies, Dr. Janet Amico for helpful advice, and Michele Macom for preparation of the manuscript. REFERENCES 1. Centers for Disease Control. HIV/AIDS surveillance report- -United States. October 1989:1-16. 2. Hopewell PC. Pneumocystis carinii pneumonia: diagnosis. J Infect Dis 1988;157:1115-1119. 3. Raviglione MC, Mariuz P, Sugar J, Mullen MP. Extrapulmonary Pneumocystis infection. Ann Intern Med 1989; 111:339. 4. Richie TL, Yamaguchi E, Virani NA, Quinn BD, Chaisson RE. Extrapulmonary Pneumocystis infection. Ann Intern Med 1989;111:339-340. 5. Case records of the Massachusetts General Hospital (case 9—1989). N Engl J Med 1989;320:582-587. 6. Girard PM, Landman R, Gaudebout C, et al. Prevention of Pneumocystis carinii pneumonia relapse by pentamidine aerosol in zidovudine-treated AIDS patients. Lancet 1989;1:1348-1353. 7. Conte JE, Hollander H, Golden JA. Inhaled or reduced dose of intravenous pentamidine for Pneumocystis carinii pneumonia: a pilot study. Ann Intern Med 1987;107:495-498. 8. Gallant JE, Enriquez RE, Cohen K.L, Hammers LW. Pneumocystis carinii thyroiditis. Am J Med 1988;84:303-306. 9. Lopresti JS, Fried JC, Spencer CA, Nicoloff JT. Unique alternations of thyroid hormone indices in the acquired immunodeficiency syndrome (AIDS). Ann Intern Med 1989; 110:970-975. 10. Kapadia SB, Dekker A, Cheng VS, Desai UMA, Watson CG. Malignant lymphoma of the thyroid gland: a clinicopathologic study. Head Neck Surg 1982;4:270-280. 11. Ragni MV, Lewis JH, Bontempo FA, Spero JA. Lymphoma presenting as a traumatic hematoma in an HTLV-II1 antibody positive hemophiliac. N Engl J Med 1985;313:640. 12. Campbell WG. Ultrastructure of Pneumocystis in human beings. Arch Pathol 1972;93:312-324. 13. Cupples JB, Blackie SP, Road JD. Granulomatous Pneumocystis carinii pneumonia mimicking tuberculosis. Arch Pathol Lab Med 1989:113:1281. Malignant Peritoneal Mesothelioma in Childhood with Long-term Survival WILLIAM A. GEARY, M.D., P H . D . , STACEY E. MILLS, M.D., HENRY F. FRIERSON, J R . , M.D., AND THOMAS L. POPE, M.D. A diffuse, well-differentiated, malignant peritoneal mesothelioma (MPM) developed in a nine-year-old girl. She received limited chemotherapy and radiation therapy and is alive and well without clinical evidence of disease 109 months after diagnosis. The neoplastic cells stained immunohistochemically for cytokeratin and epithelial membrane antigen but were unreactive with B72.3, anti-carcinoembryonic antigen, and anti-Leu-Ml. Ultrastructurally, the tumor cells had abundant desmosomes, numerous tonofilament bundles, and variable-length microvilli. These findings confirm the mesothelial nature of the cells. Features con- sistent with malignancy included DNA aneuploidy by flow cytometric analysis and diffuse peritoneal involvement. The three previously described survivors with MPM were also premenarchal girls. Some MPMs in premenarchal girls have an indolent biologic behavior similar to that of low-grade peritoneal serous neoplasia or well-differentiated papillary mesothelioma in adult women. (Key words: Mesothelioma; Childhood; Immunohistochemistry; Flow cytometry; DNA analysis; Peritoneum; B72.3; Leu-Ml; Carcinoembryonic antigen; Cytokeratin; Epithelial membrane antigen) Am J Clin Pathol 1991;95:493-498 Most malignant peritoneal mesotheliomas (MPMs) occur men, many of whom have a history of asbestos exposure.12 Long-term survival in adults with MPMs is distinctly uncommon. The rare MPMs occurring in childhood have several important clinical differences from their adult counterparts.3"7 In children, MPMs have no clearcut association with asbestos exposure and no male predilection. Furthermore, isolated examples of survival in From the Departments of Pathology and Radiology. University of Virin ginia Health Sciences Center, Charlottesville, Virginia. Received April 19, 1990; received revised manuscript and accepted for publication July 12, 1990. Dr. Pope is currently a member of the Department of Radiology, Bowrri£.:i Gray Medical Center, Winston-Salem, North Carolina. Address reprint requests to Dr. Mills: Department of Pathology, Box 214, University ofVirginia Health Sciences Center, Charlottesville, Virginia 22908. Vol. 95 • No. 4