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Primary primitive neuroectodermal tumor of the cauda equina
Case Studies PRIMARY PRIMITIVE NEUROECTODERMAL TUMOR OF THE CAUDA EQUINA PHILLIP A. ISOTALO, MD, CHARLES AGBI, MD, FRCSC, BARRY DAVIDSON, MD, FRCPC, ANDRE GIRARD, MD, FRCPC, SHAILENDRA VERMA, MD, FRCPC, AND SUSAN J. ROBERTSON, MD, FRCPC Primitive neuroectodermal tumors (PNETs) are aggressive neoplasms composed predominantly of undifferentiated cells that show evidence of neural differentiation. Although their classification has been controversial, PNETs are well recognized primary tumors of both central and peripheral nervous systems. PNETs must be distinguished from other round-cell tumors, including Ewing’s sarcoma, lymphoma, rhabdomyosarcoma, and small cell carcinoma. Intraspinal PNETs are rare neoplasms that are usually metastatic in origin. We describe the eighth reported primary PNET of the cauda equina that developed in a 52-year-old man with no significant medical history. The tumor was characterized by Homer-Wright rosettes and immunoreactivity for CD99, glial fibrillary acidic protein, neuron-specific enolase, S100, and synaptophysin. The anatomic location of primary
intrathecal PNETs is important as those arising in the spinal cord develop in the central nervous system, whereas those arising in the cauda equina develop in the peripheral nervous system. The histogenesis of intrathecal PNETs may be multifactorial. HUM PATHOL 31: 999-1001. Copyright © 2000 by W.B. Saunders Company Key words: primitive neuroectodermal tumor, small round-cell tumor, neoplasm, cauda equina. Abbreviations: PNET, primitive neuroectodermal tumor; MRI, magnetic resonance imaging; H&E, hematoxylin and eosin; HPS, hematoxylin phloxine saffron; PAS, periodic-acid Schiff; EMA, epithelial membrane antigen; LCA, leukocyte common antigen; NSE, neuron-specific enolase; CNS, central nervous system.
Primitive neuroectodermal tumors (PNETs) are malignant neoplasms whose classification has been controversial since their description in 1973 by Hart and Earle.1 These tumors are composed of predominantly undifferentiated cells and in the cerebellum have been traditionally known as medulloblastomas.2,3 PNETs may also arise in the cerebrum, the brainstem, the pineal gland, the spinal cord, and peripheral nerves.1-13 Primary intraspinal PNETs are rare and can arise as intramedullary, extramedullary, or extradural tumors at any level of the spinal cord.4-5 Primary PNETs of the cauda equina are even less common.6-10 We describe the eighth reported primary PNET of the cauda equina in a 52-year-old man with no significant past medical history.
intrathecal tumor that extended from the L2-L3 disc space caudally to the inferior body of L5 (Fig 1). This tumor appeared to encase, rather than displace, the spinal nerve roots and specifically did not involve the conus medullaris. The radiological growth pattern of the tumor was highly suggestive of an ependymoma. MRI of the brain with gadolinium enhancement was normal. At surgery, a soft, friable, intrathecal tumor was confirmed underlying atrophic dura. The tumor encased the spinal nerve roots and displaced some of the roots laterally and others posteriorly. Intraoperative frozen section showed a necrotic, undifferentiated, small round-cell tumor, and a PNET was diagnosed on permanent sections. Microsurgical excision of the tumor was performed; however, tumor debulking was only possible, as the tumor was intricately associated with many of the nerve roots. The patient had an uncomplicated postoperative course, and his neurological symptoms gradually improved. After his surgical wound had healed, he received whole central nervous system irradiation with a total dose of 3,850 cGy, followed by a radiation dose of 1,750 cGy directed at the tumor. The tumor was radiosensitive, and a year after the discovery of his intrathecal neoplasm, the patient has had no clinical or radiological evidence of tumor recurrence.
CASE REPORT A 52-year-old man presented to the Ottawa General Hospital with a 6-month history of progressive back pain and difficulty in ambulating and a 2-week history of post-voiding urinary incontinence and numbness in the caudal area. Physical examination confirmed decreased sensation to pinprick in the L4-S2 distributions on the left side and in the S1-S2 distributions on the right side. The patient had markedly decreased anal sphincter tone, marked limitation of straight leg raising bilaterally, and grade 3/5 weakness of dorsiflexion in his left leg. He had diminished knee jerk reflexes bilaterally. The patient was diagnosed with an incomplete cauda equina syndrome. Emergency magnetic resonance imaging (MRI) of the spine with gadolinium enhancement showed a 10-cm long
From the Departments of Laboratory Medicine, Anatomical Pathology, Neurosurgery, Surgery, Radiology, Radiation Oncology, Medical Oncology, and Internal Medicine, Ottawa Hospital-General Campus, and University of Ottawa, Ottawa, Ontario, Canada. Address correspondence and reprint requests to Susan J. Robertson, MD, FRCPC, Anatomical Pathology, Ottawa Hospital-General Campus, 501 Smyth Road, Ottawa, Ontario, Canada K1H 8L6. Copyright © 2000 by W.B. Saunders Company 0046-8177/00/3108-0017$10.00/0 doi: 10.1053/hupa.2000.16532
MATERIALS AND METHODS Biopsy specimens were fixed in 10% buffered formalin after a representative section was submitted for frozen section. Paraffin-embedded tissue was stained with hematoxylin and eosin (H&E) and hematoxylin phloxine saffron (HPS). Periodic acid-Schiff (PAS) stains with and without diastase digestion were performed. Immunohistochemistry was performed on 4- thick deparaffinized tissue sections using an avidin-biotin horseradish peroxidase method and antibodies directed against CD20 (1:400 dilution; DAKO, Carpinteria, CA), CD45RO (1:50; DAKO), CD57 (1:50; Becton Dickinson, San Jose, CA), CD99 (1:100; DAKO), chromogranin (1:500; Biogenix, San Ramon, CA), cytokeratin CAM 5.2 (1:200; Becton Dickinson, Mississauga, Canada), desmin (1:500; DAKO), epithelial membrane antigen (EMA; 1:750; DAKO), glial
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FIGURE 1. Primary primitive neuroectodermal tumor of the cauda equina. Sagittal magnetic resonance imaging scan enhanced with gadolinium showing an intrathecal tumor extending from the L2-L3 disc space caudally to the inferior body of L5. There is no involvement of the conus medullaris by tumor.
development of PNETs.1,11-12 In their examination of cerebral PNETs, Hart and Earle1 restricted their definition of PNET to tumors containing 90% to 95% undifferentiated cells. This concept of PNET was expanded by Becker and Hinton3 and Rorke2 when they proposed classifying all central nervous system (CNS) tumors with a predominant undifferentiated, primitive cell component as PNETs. This classification of PNET has been controversial, and the recent World Health Organization classification of brain tumors avoids this controversy by recommending that PNET be used as a “generic term” for cerebellar medulloblastomas and other CNS tumors that are morphologically identical to medulloblastoma.11-12 It is also well recognized that PNETs are not only restricted to the CNS but that they may also arise along peripheral nerves.3,6-10,13 PNETs are classified as small, round-cell tumors and must be distinguished from similar tumors that include extraskeletal forms of Ewing’s sarcoma, lymphoma, rhabdomyosarcoma, and small-cell carcinoma.6,9,13-15 PNETs are undifferentiated neoplasms characterized by small, uniform, round cells with hyperchromatic nuclei that show evidence of neural differentiation.6,13-15 The diagnosis of PNET is dependent on the identification of either Homer-Wright or Flexner-Wintersteiner rosettes.6,13-14 No specific criteria exist for the quality or quantity of rosettes, and some PNETs may show only
fibrillary acidic protein (GFAP; 1:750; DAKO), leukocyte common antigen (LCA; 1:400; DAKO), neurofilaments (1: 100; DAKO), neuron-specific enolase (NSE; 1:500; DAKO), S100 (1:75; DAKO), serotonin (1:100; DAKO), somatostatin (1:100; DAKO), synaptophysin (1:100; Biogenix), and vimentin (1:100; DAKO). PATHOLOGICAL FINDINGS A necrotic, undifferentiated, round-cell tumor was identified at frozen section. On permanent H&E stained sections, the tumor was characterized by small undifferentiated cells with distinct, but scant, cytoplasm and hyperchromatic nuclei that showed margination of chromatin and inconspicuous nucleoli. Undifferentiated round cells formed occasional Homer-Wright rosettes (Fig 2). No ependymal type perivascular rosettes were identified. Mitotic figures and apoptotic tumor cells were both prominent. Focal tumor cells contained glycogen, as shown by PAS-positive intracytoplasmic granules that disappeared after diastase digestion. No ganglion cells were identified. The round-cell tumor exhibited strong immunohistochemical staining for synaptophysin, CD99 (Fig 3), and vimentin and focal staining for GFAP, NSE, and S100. Immunohistochemical stains directed against CD20, CD45RO, CD57, cytokeratin CAM 5.2, chromogranin, desmin, EMA, LCA, neurofilaments, serotonin, and somatostatin were all negative. The histologic and immunohistochemical features of this undifferentiated round-cell tumor were consistent with a diagnosis of PNET. DISCUSSION PNETs are generally regarded as embryonal tumors whose histogenesis is both unknown and possibly multifactorial.1,11 PNETs are thought to arise from immature progenitor cells; however, the exact cell of origin has not been identified. Multiple histogenetic theories have been proposed for the
FIGURE 2. Photomicrograph of the primitive neuroectodermal tumor with a Homer-Wright rosette and prominent mitotic figures. (HPS stain, original magnification ⫻400.)
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tant, as the cauda equina is essentially part of the peripheral nervous system, where spinal nerve root axons have already exited the cord and have become dependent on Schwann cells for the maintenance of their myelin sheaths.9 Our patient had a PNET arising in the cauda equina that was confirmed to be primary in origin. This tumor showed evidence of neural differentiation characterized by well formed Homer-Wright rosettes and immunoreactivity for synaptophysin, NSE, S100, and GFAP. The immunohistochemical phenotype of the tumor was inconsistent with any round-cell tumor other than PNET. Tumor expression of CD99 was evidence of a PNET/Ewing family of tumors. GFAP expression by this PNET was particularly interesting, as immunoreactivity for this neural marker, along with chromogranin, is considered evidence of more mature neural differentiation.15 A previous study by Brinkhuis et al15 suggested that the use of both chromogranin and GFAP was of limited value in the diagnosis of PNETs. Our patient’s tumor did not express any immunoreactivity for chromogranin. The accurate diagnosis of PNETs is important, as these are aggressive neoplasms.4,12-13 The distinction between PNET and Ewing’s sarcoma is also important, as PNETs are thought to carry a worse prognosis.15 No standard therapy exists for spinal cord or cauda equina PNETs, although many patients have been treated with a combination of chemotherapy, radiotherapy, and surgery.4 Unfortunately, even with therapy, patient prognosis is poor and survival beyond 2 years is rare. Our patient continues to be followed closely for evidence of tumor recurrence. Acknowledgment. We would like to thank Dr L. E. Becker of The Hospital for Sick Children’s Department of Pathology, Toronto, Canada, for his review of this case.
REFERENCES
FIGURE 3. Primitive neuroectodermal tumor cells expressing strong immunoreactivity for the surface glycoprotein CD99. (Immunohistochemical stain for CD99, original magnification ⫻600.)
abortive rosette forms.6,14 Other diagnostic features of PNETs include the rare identification of ganglion cells, reactivity for 2 or more neural immunohistochemical markers, and ultrastructural evidence of neural differentiation.6,13-15 Peripheral PNETs and Ewing’s sarcomas are thought to be closely related tumors, as they have the same reciprocal chromosomal translocation t(11;22)(q24:q12), similar tumor expression of the glycoprotein CD99, and they share expression of the same oncogenes, including c-myc, c-myb, c-ets-1, and N-myc.6,14-15 Evidence of neural differentiation in PNETs is the phenotypic feature that differentiates these tumors from Ewing’s sarcoma.14-15 Although PNETs are common in the pediatric population, occurring primarily as cerebellar medulloblastomas, PNETs are rare in adults, especially presenting as spinal cord or cauda equina tumors.3-10,12-13 The majority of PNETs that involve the cord or the spinal nerve roots are metastatic in origin and are the result of “drop” metastases from tumors more superior in the neruroaxis.4,9 Any intraspinal PNET must be considered a metastatic tumor until proven otherwise.7 Only 14 primary PNETs of the spinal cord and 7 primary PNETs of the cauda equina have been described previously.4-10 The distinction between these 2 sites is impor-
1. Hart MN, Earle KM: Primitive neuroectodermal tumors of the brain in children. Cancer 32:890-897, 1973 2. Rorke LB: The cerebellar medulloblastoma and its relationship to primitive neuroectodermal tumors. J Neuropathol Exp Neurol 42:1-15, 1983 3. Becker LE, Hinton D: Primitive neuroectodermal tumors of the central nervous system. HUM PATHOL 14:538-550, 1983 4. Deme S, Ang L-C, Skaf G, et al: Primary intramedullary primitive neuroectodermal tumor of the spinal cord: Case report and review of the literature. Neurosurgery 41:1417-1420, 1997 5. Papadatos D, Albrecht S, Mohr G, et al: Exophytic primitive neuroectodermal tumor of the spinal cord. Am J Neuroradiol 19:787-789, 1998 6. Hisaoka M, Hashimoto H, Murao T: Peripheral primitive neuroectodermal tumour with ganglioneuroma-like areas arising in the cauda equina. Virchows Arch 431:365-369, 1997 7. McDermott VGM, El-Jabbour JN, Sellar RJ, et al: Primitive neuroectodermal tumour of the cauda equina. Neuroradiology 36:228-230, 1994 8. Liu H-M, Yang WC, Garcia RL, et al: Intraspinal primitive neuroectodermal tumor arising from the sacral spinal nerve root. J Comput Tomogr 11:350-354, 1987 9. Kepes JJ, Belton K, Roessman U, et al: Primitive neuroectodermal tumors of the cauda equina in adults with no detectable primary intracranial neoplasm—three case studies. Clin Neuropathol 4:1-11, 1985 10. Smith DR, Hardman JM, Earle KM: Metastasizing neuroectodermal tumors of the central nervous system. J Neurosurg 31:50-58, 1969 11. Kleihues P, Burger PC, Scheithauer BW: The new WHO classification of brain tumours. Brain Pathol 3:255-268, 1993 12. Lantos PL, VandenBerg SR, Kleihues P: Tumours of the nervous system, in Graham DI, Lantos PL (eds): Greenfield’s Neuropathology. London, Arnold, 1997, pp 583-879 13. Enzinger FM, Weiss SW: Primitive neuroectodermal tumors and related lesions, in Enzinger FM, Weiss SW (eds): Soft Tissue Tumors. St Louis, Mosby, 1995, pp 929-964 14. Dehner LP: Primitive neuroectodermal tumor and Ewing’s sarcoma. Am J Surg Pathol 17:1-13, 1993 15. Brinkhuis M, Wijnaendts LCD, van der Linden JC, et al: Peripheral primitive neuroectodermal tumour and extra-osseous Ewing’s sarcoma: A histological, immunohistochemical and DNA flow cytometric study. Virchows Arch 425:611-616, 1995
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SUDDEN CARDIAC DEATH OWING TO PSEUDOXANTHOMA ELASTICUM: A CASE REPORT KURT B. NOLTE, MD A 26-year-old woman collapsed and died suddenly while dancing. Autopsy findings included the cutaneous lesions of pseudoxanthoma elasticum (PXE), a rare genetic disease with autosomal dominant and recessive inheritance patterns. Pathologic findings of PXE (degenerated elastic fibers) were seen in the stenotic epicardial coronary arteries, the intramyocardial arterioles, the subendocardium, the mitral valve, and the blood vessels of other viscera. The mitral valve was slightly myxoid. Intramyocardial arteriolar involvement has not been previously described in PXE. The other cardiac findings have only been described in a few cases. Although mitral valve prolapse in PXE has been shown echocardiographically, it is unclear whether or not
the mitral valve findings in this case represent the substrate for this condition. It is important that autopsy pathologists search carefully for the pathognomonic skin lesions of PXE in cases of sudden death associated with coronary disease, mitral valve prolapse, or endocardial lesions. Recognition of this disease is essential for proper genetic counseling of surviving family members. HUM PATHOL 31:1002-1004. Copyright © 2000 by W.B. Saunders Company Key words: pathology, pathophysiology, forensic science, pseudoxanthoma elasticum, mortality, autopsy, cardiac disease. Abbreviations: PXE, pseudoxanthoma elasticum; LAD, left anterior descending; LCX, left circumflex.
Pseudoxanthoma elasticum (PXE) is a rare, inherited, systemic disease of elastic tissue that especially affects the skin, eyes, and cardiovascular system. The prevalence of the disease is estimated at 1 in 100,000 population, about the same frequency as Marfan’s syndrome. No racial or geographic predominance has emerged. PXE is inherited through both autosomal recessive (90%) and autosomal dominant (10%) patterns. There is no known genetic marker. The pathologic feature of this disease is central calcification and fragmentation of fully developed elastic fibers. The primary defect and pathogenesis are unknown but may include the synthesis of abnormal elastic fibers which subsequently calcify; and the alteration of normal elastic fibers by acid mucopolysaccharides, proteases or other substances resulting in calcification.1 Although the cutaneous and ocular pathology of PXE is well described, only a few autopsy cases with cardiac involvement are reported. These cases have changes in the coronary arteries, endocardium, valves, and conducting system.2-11 Corresponding clinical manifestations of PXE include angina, congestive heart failure, and mitral valve prolapse.12-14 This report describes a case of sudden death owing to cardiac involvement by PXE and details the pathologic findings.
normal appearing collagen bundles. This material stained positively for elastic tissue with a Verhoeff-van Gieson stain and for calcium with a Von Kossa stain. The heart weighed 220 g. The coronary arteries were normally distributed with a dominant right coronary artery. All of the epicardial coronary arteries were of small caliber and were concentrically narrowed. The right and the left main coronary arteries had an external diameter of 4 mm and a luminal diameter of 2 mm. The left anterior descending (LAD) branch had an external diameter of 4 mm and a proximal luminal diameter of 2 mm. At 1.5 cm from the origin, the LAD tapered to a pinpoint lumen (narrowed by greater than 95% cross sectional area). The left circumflex (LCX) branch had an external diameter of 2 mm and a proximal luminal diameter of 1 mm. At 1.5 cm from the origin, the LCX also tapered to a pinpoint lumen (narrowed by greater than 95% cross sectional area). The intima of these vessels appeared focally yellow and myxoid. There were focal yellow-white endocardial streaks in the right atrium (Fig 1). The tricuspid, pulmonic, and aortic valves were normal. The mitral valve showed slightly myxoid leaflets with moderate interchordal hooding. The chordae tendineae appeared normal. The myocardium was dark brown and without ischemic change. The aorta showed a few yellow intimal streaks. Microscopic sections of the coronary arteries, the left anterior descending coronary vein, and the renal and adrenal arterioles showed myxoid intimal fibrosis and fragmentation of the elastica with degenerated, calcified fibers identical to
CASE REPORT A 26-year-old woman collapsed suddenly while dancing. An electrocardiogram showed ventricular fibrillation. Resuscitation efforts were unsuccessful. Autopsy findings included confluent yellow papules and plaques with a “chicken skin” appearance over the anterior and posterior neck, throughout the inguinal regions, in the antecubital fossae, and around the umbilicus. Microscopic sections of the skin lesions showed basophilic granular material in the middle and deep dermis interspersed between
From the Office of the Medical Investigator, University of New Mexico School of Medicine, Albuquerque, NM; and Medical Examiner/Coroner Information Sharing Program, Surveillance and Programs Branch, Division of Environmental Hazards and Health Effects, National Center for Environmental Health, Centers for Disease Control and Prevention, Atlanta, GA. Presented at the 23rd Annual Meeting, National Association of Medical Examiners, Sanibel Island, FL, 1989. Address correspondence and reprint requests to Kurt B. Nolte, MD, Office of the Medical Investigator, University of New Mexico School of Medicine, Albuquerque, NM 87131-5091. Copyright © 2000 by W.B. Saunders Company 0046-8177/00/3108-$10.00/0 doi: 10.1053/hupa.
FIGURE 1.
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the elastic fibers of the skin lesions (Figs 2A, B). No lipid deposits were present. Similar collections of degenerated elastic fibers were seen in the subendocardium of the right atrium, left atrium, and left ventricle (Fig 3) and were widespread within the mitral valve. The elastic laminae of intramyocardial arterioles were extensively calcified and fragmented without intimal changes. Adjacent to the His bundle and left bundle branch fibers were focal calcifications. The aorta showed focally fragmented calcified elastic fibers within the media. The remainder of the viscera was unremarkable. The cause of death was listed as “cardiac ischemia due to abnormal coronary arteries due to pseudoxanthoma elasticum.” A subsequent discussion with the decedent’s husband showed that PXE had been previously diagnosed in both the decedent and her sister. In this family, the disease was thought to follow an autosomal recessive inheritance pattern. DISCUSSION Coronary involvement by PXE has potentially lethal consequences. In 2 large clinical series, 13% and 52% of PXE patients had angina pectoris.1,5 Coronary pathology similar to that noted in this case is likely the underlying cause of the angina pectoris often present in these patients. Of 17 postmortem PXE hearts described in the English language liter-
FIGURE 3. Collection of degenerated elastic fibers in the atrial subendocardium. (Verhoeff-van Gieson stain, original magnification 100⫻.)
FIGURE 2. Left anterior descending coronary artery with (A) myxoid intimal fibrosis and fragmented, calcified, elastic lamina (hematoxylin and eosin stain, original magnification 100⫻) and (B) degenerated elastic fibers indicated by arrows (Verhoeff-van Gieson stain, original magnification 400⫻).
ature, 13 (76%) had some degree of coronary “atherosclerosis” or calcification.2-11 Two of the 13 cases had a calcified and fragmented coronary elastica similar to the lesions identified in this report.7,10 Pathologic segments of coronary artery removed during bypass grafting from 2 young women with PXE and angina showed similar changes, with a calcified internal elastic lamina in 1 case12 and disrupted elastic laminae, myxoid subendothelial thickening, and medial fibrosis in the other case.15 The presence of these histologic findings, especially in very young individuals, and the absence of lipids from the lesions suggest PXE of the coronary arteries rather than early atherosclerosis. Degeneration of blood vessels in PXE is probably a generalized process as up to 45% of patients with the disease have claudication.1,5 In the present case, PXE degeneration was evident in adrenal and renal arterioles, aorta, and a coronary vein, in addition to the coronary arteries. Mitral valve prolapse has been identified by echocardiogram in 71% of patients with PXE.13 Calcified or thickened valves are described in 4 other cases, but details are lacking.4,5,8 The case described here had an abnormal mitral valve with disrupted elastic fibers. Whether or not this is the substrate for mitral valve prolapse in PXE is unknown. Endocardial lesions similar to those seen in this case have been shown in 8 other cases,4-6,8-10 including 1 case where the bundle
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branches were encased in the thickened endocardium.10 Endocardial PXE can lead to restrictive cardiomyopathy.6 Congestive heart failure is frequently described in PXE and is a potential consequence of ischemic, valvular, or restrictive endocardial disease.6-10,12 As seen in this case, another possible etiology of both congestive failure and angina in PXE is cardiac intramural arteriolar degeneration. Although this condition has not been previously described pathologically, intramural coronary artery involvement was suspected clinically as the cause of angina and congestive failure in a PXE patient with angiographically normal epicardial vessels and fragmented endocardial elastica on biopsy.14 This case illustrates that sudden death owing to cardiac PXE has a range of potential pathophysiological mechanisms. Fatal arrhythmias may be owing to large- or small-vessel coronary stenosis with ischemia, conducting system, and endocardial disruption by degenerated elastic fibers, or mitral valve prolapse. Sudden death associated with PXE has only been described in 3 previously asymptomatic boys who collapsed during exercise.2 One boy had coronary artery changes and another boy had endocardial involvement. No autopsy was performed in the third case. Although the cutaneous lesions of PXE are of cosmetic importance, they also serve as a marker for potentially fatal cardiovascular disease, especially in young people. Therefore, it is important that autopsy pathologists search carefully for the pathognomonic skin lesions in cases of sudden death associated with coronary disease, mitral valve prolapse, or endocardial lesions. Recognition of this disease is essential for proper genetic counseling of surviving family members. Acknowledgment.
The author is grateful to James L. Luke,
MD, Ross E. Zumwalt, MD, and Bronwyn E. Wilson, MD, for editorial comments and direction. REFERENCES 1. Neldner KH: Pseudoxanthoma elasticum. Clin Dermatol 6:1-159, 1988 2. Wilhelm K, Paver K: Sudden death in pseudoxanthoma elasticum. Med J Aust 2:1363-1365, 1972 3. Hamilton-Gibbs JS: Death from coronary calcinosis occurring in the baby of a mother presenting with pseudoxanthoma elasticum. Australas J Dermatol 11:145-148, 1970 4. McKusick VA: Heritable Disorders of Connective Tissue. St Louis, MO, Mosby Co, 1972, pp 475-520 5. Carlborg U, Ejrup B, Gronblad E, et al: Vascular studies in pseudoxanthoma elasticum and angioid streaks. Acta Medica Scand 166:1-84, 1959 6. Navarro-Lopez F, Llorian A, Ferrer-Roca O, et al: Restrictive cardiomyopathy in pseudoxanthoma elasticum. Chest 78:113-115, 1980 7. Perrot LJ, Mrak RE: Cardiac involvement in a child with unsuspected pseudoxanthoma elasticum. Pediatr Pathol 13:273-279, 1993 8. Coffman JD, Sommers SC: Familial pseudoxanthoma elasticum and valvular heart disease. Circulation 19:242-250, 1959 9. Mendelsohn G, Bulkley BH, Hutchins GM: Cardiovascular manifestations of Pseudoxanthoma elasticum. Arch Pathol Lab Med 102:298-302, 1978 10. Huang S, Kumar G, Steele HD, et al: Cardiac involvement in pseudoxanthoma elasticum. Report of a case. Am Heart J 74:680-686, 1967 11. Milstoc M: An unusual anatomo-pathologic aspect of a case with pseudoxanthoma elasticum. Dis Chest 55:431-434, 1969 12. Lebwohl M, Halperin J, Phelps RG: Brief report: Occult pseudoxanthoma elasticum in patients with premature cardiovascular disease [see comments]. N Engl J Med 329:1237-1239, 1993 13. Lebwohl MG, Distefano D, Prioleau PG, et al: Pseudoxanthoma elasticum and mitral-valve prolapse. N Engl J Med 307:228-231, 1982 14. Przybojewski JZ, Maritz F, Tiedt FA, et al: Pseudoxanthoma elasticum with cardiac involvement. A case report and review of the literature. S Afr Med J 59:268-275, 1981 15. Bete JM, Banas JS, Jr, Moran J, et al: Coronary artery disease in an 18-year-old with pseudoxanthoma elasticum: Successful surgical therapy. Am J Cardiol 36:515-520, 1975
BOOK REVIEWS Pathology for the Health-Related Professions (ed 2). Ivan Damjanov. Philadelphia, PA, W.B. Saunders Company, 2000, 545 pages, $52.00. A key element in the education of allied health professionals is the development of an understanding of the disease process. Professors engaged in the teaching of pathology to this group of students have long struggled with the need for a textbook directed specifically at this audience. While many textbooks purport to be designed for this purpose, an examination of their contents generally shows them to be insufficient in some manner. Some are digests of larger, more detailed texts, and as such, do not read well. Others turn out to be mere surveys of human disease and do not allow the student to develop an understanding of the pathophysiologic processes involved. Yet another group delves too deeply into pathophysiology, leaving undergraduate allied health students gasping and frustrated. Publication of the first edition of Pathology for the HealthRelated Professions by Ivan Damjanov in 1996 filled the need for a textbook written for this specific audience. Although an excellent text, as with most first editions, there were areas which could be improved. Examination of the recently published second edition of this text shows that attention has been paid to the suggestions undoubtedly made by faculty
and students using this resource. Thankfully, the underlying character of the text has been maintained and enhanced. The author’s obvious enthusiasm for his subject is conveyed in a manner which encourages the reader and promotes a desire for understanding of the subject. Our best students will invest their time in reading even the driest of textbooks, and they are not a difficult group to teach. It is the next tier of students, those who have ability but lack motivation, that are the greatest challenge to textbook authors and classroom professors. For those students, a book must not merely contain the required information, it must be presented in a highly accessible manner. It is a further benefit if the text is somewhat entertaining. The author accomplishes this feat in Pathology for the Health-Related Professions. Damjanov has the ability to describe pathologic processes as one would tell a story, encouraging the student to continue reading beyond merely the assigned topic or pages. Of particular help in this regard are sidebars contained in boxes entitled “Did you know?” which place the topic under discussion in historical or popular context. I have observed students thumbing through specifically looking for these boxes and the information they contain. As in the first edition, this book begins with a review of cell biology and discussion of cell pathology. One can not begin to understand the disease process until an understanding of the cell is accomplished. Without this foundation,
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organs are merely “black boxes” in which magic happens (or, in the case of disease, goes awry). The author has further illuminated his discussion of this topic by making the illustrations in this section more colorful and appealing. In fact, one of the main improvements in the second edition is the addition of color to many of the previously black and white or half-tone illustrations. This seemingly minor change tends to draw the readers’ eye and deliver the information with remarkable clarity. A common misconception among textbook writers and perhaps among educators is that photomicrographs are the most efficient way of showing histopathology. In fact, I have often observed students struggling with photomicrographs of structures which could be more clearly conveyed by illustrations. I have frequently resorted to drawing the structure in question, to help the student understand the photomicrograph. In the second edition of Pathology for the Health-Related Professions, the author has replaced several problematic photomicrographs with illustrations. This again is a notable improvement. Subsequent chapters deal with Inflammation, Immunopathology, Neoplasia, Genetic and Developmental Diseases, Fluid, and Hemodynamic Disorders. Later chapters follow a systemic approach to disease and apply the basics learned in the earlier chapters. As each disease is presented, a brief introductory discussion leads to topics such as Etiology and Epidemiology, Pathogenesis, Clinical Presentation, Pathologic Findings, and Treatment. This enables the student to quickly find the information needed. This ease of use is further aided by the listing of Learning Objectives, and Additional Key Terms and Concepts at the beginning of each chapter. While this text aptly fills the needs of students of the allied health professions, its ease of presentation and colorful illustrations make it a valuable resource to many in the medical community.—ROBERT K. CLARK, PHD, Associate Professor, Division of Health and Sciences, Cumberland County College, Vineland, NJ. Bone and Soft Tissue Tumors. Mario Campanacci. Wien, NY, Springer-Verlag, 1999, 1,319 pages. The second edition of the late Dr Campanacci’s book represents an almost entirely new book rather than an update of the first edition. As stated in the Preface, the book has been rewritten in English (as opposed to the first edition which was translated from Italian) and incorporates a number of new illustrations, the most noticeable of which are updated magnetic resonance images. These changes have resulted in a wonderfully written, almost encyclopedic text on bone and soft tissue tumors. The book is divided into 3 segments. The first is an introduction to general concepts, including terminology, radiographic principles, grading and staging, surgical margins, and treatment. The information provided on surgical mar-
gins and the Enneking/Musculoskeletal Tumor Society staging system is particularly useful for pathologists not familiar with these concepts. The second segment, which accounts for approximately two thirds of the book, is devoted to tumors and tumor-like lesions of bone. Dr Campanacci’s experience and the wealth of material available at the Rizolli Institute are quite evident, as virtually all entities known to occur in bone are covered. The discussion of each individual lesion begins with a definition of the entity followed by detailed information regarding epidemiology and location, including figures depicting the Rizolli Institute’s experience with the tumor in question. Next, clinical information, radiographic features, and gross and histopathologic findings are presented, each complemented by a wealth of black and white photographs. For pathologists not experienced in interpretation of radiographic studies, the book offers numerous examples and variations of the radiologic features of each entity. Each chapter is completed with a detailed discussion of differential diagnosis, treatment, and prognosis. Several chapters are particularly informative, including those on osteofibrous dysplasia and adamantinoma, and those devoted to central and surface osteosarcomas. The third segment of the book covers tumors and tumorlike conditions of soft tissue. While most tumors and tumorlike conditions are presented, they are not covered nor illustrated in the depth of the osseous lesions. Nonetheless, sufficient information is provided on differential diagnosis and immunohistochemical staining to make these chapters useful to surgical pathologists. Furthermore, few texts are available which incorporate both bone and soft tissue lesions in a single volume. The criticisms of the book are minor and few in number. Although this book is copyrighted 1999, the majority of the references are from 1997 or earlier, with only a handful of citations from 1998. Nonetheless, most of the “classic” references for any given tumor are listed. Second, all of the photomicrographs and gross photographs are in black and white. While the illustrations are of excellent quality overall, most readers now expect color photographs, particularly given the cost of the book. Finally, although the book has been rewritten in English, there remain words and phrases which still require some clarification. These criticisms are minor and detract little from the overall excellent quality of the book. In summary, the second edition of Dr Campanacci’s book is well written and well illustrated and is a text which any surgical pathologist would find useful when faced with one of these relatively uncommon lesions, particularly those arising in bone.—JOHN D. REITH, MD, Assistant Professor, Departments of Pathology, Immunology and Laboratory Medicine and Orthopaedic Surgery, University of Florida College of Medicine, Gainesville, FL. JOHN R. GOLDBLUM, MD, Department of Anatomic Pathology, The Cleveland Clinic Foundation, Cleveland, OH.
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CORRESPONDENCE On Tiny Tissue Samples, Common Sense, and Molecular Pathology To the Editor:—For tissue-based diagnosis of disease, pathologists often have to rely on increasingly small samples. However, the following case illustrates that this is not entirely risk free. A dysplastic fragment of epithelium was seen in the endoscopic biopsy tissue of a whitish lesion in the lower esophagus from a 46-year-old woman. Consequently, the patient was kept under close surveillance. However, 4 biopsies taken in the following 9 months failed to show any abnormality and the possibility of a mix-up was raised. The mix-up in the first biopsy was proven using dysplastic (D) and normal (N1), routinely H&E stained tissue fragments (Fig 1A) scraped from the same glass slide manually with a scalpel under microscopic examination and normal tissue (N2) from a biopsy 9 months later. From these minuscule tissue fragments, DNA was extracted, and allelotyping was performed by radioactive polymerase chain reaction (PCR) of polymorphic microsatellites using 4 markers.1,2 PCR, followed
by size separation of the products was performed as described earlier.1 Biopsy specimen mix-ups can occur in many ways and many places, especially when such small biopsies are involved. One possibility is shown in Figure 1B, although it is standard procedure in our laboratory to additionally use specially designed bags with small “lumina” for processing small tissue fragments. The usefulness of molecular biological techniques to sort out mix-ups has been shown in other papers.3 In this case, we show that even from a single routinely processed and stained tissue section, sufficient DNA can be retrieved for PCR amplification, thus allowing an unequivocal conclusion. The procedure is very simple, and results can be obtained in 2 or 3 days, making this test useful whenever doubt arises with respect to the identification of the patient. We used radioactive PCR for our marker analysis, but this genotyping can also be performed with fluorochrome labeled primers (eg, Perkin Elmer amplitype amplification and typing kit; PE Applied Biosystems, Foster City, CA) making this test more applicable for routine diagnostic pathology laboratories. In addition, this case illustrates the importance of keeping an open eye with respect to the possibility of a mix-up when apparent discrepancies between histology and clinical impression, or between subsequent histological findings, occur. Despite the implementation of strict quality assurance protocols, the human factor, but also the “machine factor,” can never be absolutely 100% perfect. Acknowledgment. Mr F.L. van der Panne is acknowledged for making Figure 1B.
FIGURE 1. The left part (A) shows the autoradiographic result of the polymorphic microsatellite marker (CA repeat) D8S136. The results for the other 3 (CAGrepHAR, the human androgen receptor CAG repeat [1], the CA repeats D9S161, and TP53CA [2]), were the same. The PCR product from the dysplastic tissue DNA (lane D) was found to differ from the PCR products from the two normal tissue-derived DNA samples (lanes N1 and N2). This provides conclusive evidence that the dysplastic tissue and the normal tissue fragments are derived from 2 different patients. Both normal DNA samples have the same allelotype with these 4 markers indicating with a very high likelihood that they are derived from the same patient. The right part (B) shows the fragment of dysplastic epithelium on the glass slide (center), covered for comparison with the cover lid of the standard processing container. The diameter of the holes allowing the exchange of chemicals during routine automatic overnight tissue processing is 2 mm.
K.H. LAM, MD, PHD W.J. MOOI, MD, PHD H.F.B.M. SLEDDENS, BSC W.N.M. DINJENS, MSC, PHD Department of Pathology Josephine Nefkens Institute Erasmus University Medical Center Rotterdam Rotterdam, The Netherlands 1. Sleddens HFBM, Oostra BA, Brinkmann AO, et al: Tri-nucleotide repeat polymorphism in the androgen receptor gene (AR). Nucleic Acids Res 20:1427, 1992 2. Jones MH, Nakamura Y: Detection of loss of heterozygosity at the human TP53 locus using a dinucleotide repeat polymorphism. Genes Chromosomes Cancer 5:89-90, 1992 3. O’Brian DS, Sheils O, McElwaine, et al: Sorting out mix-ups: The provenance of tissue sections may be confirmed by PCR using microsatellite markers. Am J Clin Pathol 106:758-764, 1996
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NOTICES
NOTICES The 15th Combined Skin Pathology Course September 7-12, 2000 UMD-New Jersey Medical School, Newark, NJ Under the direction of W. Clark Lambert, MD, PhD, Wayne C. Johnson, MD, Thomas D. Griffin, MD, and Alan R. Silverman, MD. This is an intensive, comprehensive course including 4 full days and 2 partial days of lectures plus presentation of over 600 selected ‘‘known’’ and ‘‘unknown’’ microscopic slides for individual study on 200 single-head binocular microscopes. Faculty for this year’s course include Dr James H. Graham, Dr Martin Munro Black, St. John’s Institute of Dermatology, St. Thomas’ Hospital, London, UK; Dr. Martin C. Mihm, Jr, Massachusetts General Hospital, Harvard Medical School, Boston, MA; and Dr Mark R. Wick, University of Virginia, Charlottesville, VA. Tuition (including full meal service and all transportation for the duration of the course) is $925 ($625 for physicians in training). Registrations are limited; slightly higher rates will apply after September 1 if space is still available. A block of hotel rooms has been reserved at a reduced rate. For further information, please contact: UMDNJ-Center for Continuing Education (Attn: Ms. Catherine Stefanelli), P.O. Box 573, Newark, NJ 07101-0573; FAX: (973) 972-7128; TEL: (800) 227-4852 or (973) 972-4267. 21st Symposium of the International Society of Dermatopathology September 14-16, 2000 Graz, Austria The 21st Symposium of the International Society of Dermatopathology will be held in Graz, Austria, on September 14-16, 2000. The focus of the Meeting will be on ‘‘Differential Diagnosis of Benign and Malignant Tumors of the Skin.’’ In addition to formal lectures, free communications, and posters, there will be a ‘‘Self-Assessment Course in Dermatopathology of Cutaneous Tumors’’ conducted by an international faculty of experts in the field. One of the main topics of the Meeting will be a ‘‘Tutorial on Melanocytic Lesions’’ consisting of 100 melanocytic tumors representing difficult cases or cases with special teaching value, to which each registrant can participate submitting one or more cases. For further information, please contact: Lorenzo Cerroni, MD, Department of Dermatology, University of Graz, Auenbruggerplatz 8, A-8036 Graz, Austria. TEL: ⫹43-316-385-2371; FAX: ⫹43316-385-2466; EMAIL: [email protected]. 9th Dermatopathology Self-Assessment Workshop September 15-16, 2000 Catholic University Medical School (Istituti Biologici), Largo F. Vito, Rome, Italy Lecturers: (C.D.M. Fletcher (Harvard University, Boston, MA), R.L. Barnhill (Pathology Services, Boston, MA). Forty cases of connective tissue neoplasms and 40 cases of melanocytic skin neoplasms will be provided and illustrated respectively by Prof. Fletcher and Prof. Barnhill. During the meeting and the days before, histological slides of all cases will be available for hands-on educational sessions at the microscope. The meeting will be the occasion for short updatings about a few newly described mesenchimal and melanocytic neoplasms of the skin.
Official Language: English Cost: $200.00. For further information, please contact: Guido Massi, MD, Department of Pathology, Catholic University Medical School, Largo F. Vito, 1-00168 Rome, Italy. TEL: ⫹39-06-305-2345, 350-3481; FAX: ⫹39-06-305-1343. EMAIL: [email protected]. 3rd Teupitz Colloquium: ‘‘Basic Research in Endocrine Dermatology’’ September 17-20, 2000 Teupitz Castle Hotel (near Berlin, Germany) For further information, please contact: Prof. Dr. Ch. C. Zouboulis, Department of Dermatology, University Medical Center Benjamin Franklin, The Free University of Berlin, Hindenburgdamm 30, 12200 Berlin, Germany. TEL: ⫹4930-84 45 28 08; FAX: ⫹49-30-84 45 42 62; EMAIL: [email protected]. 2nd Joint International Workshop: ‘‘Histologic and Cytologic Characterization of Human Tumors: Borderline Neoplasia’’ September 27-30, 2000 Hotel La Palma, Capri, Italy Workshop Chairpersons: Marluce Bibbo, MD, ScD, FIAC; Giovan Giacomo Giordano, MD, PhD; and Pietro Micheli, MD, PhD Scientific Secretary: Giulia Giordano, MD, PhD. TEL: ⫹39.081.575.06.33; FAX: ⫹39.081.575.05.10; EMAIL: [email protected]. Lecturers include: J. Rosai, MD; E. Solcia, MD; A. Carbone, MD; H. Battifora, MD; M. Bibbo, MD; J.L. Connelly, MD; C. Fenoglio-Preiser, MD; F. Gorstein, MD; R. Kurman, MD; E. Rubin, MD; R. Rubin, MD; P. Tosi, MD; A. Giordano, MD Program: Plenary sessions and slide seminars on ‘‘Borderline Malignancies of Cervix, Endometrium’’; ‘‘Atypical Cells of Undetermined Significance in Pap Smears’’; ‘‘Borderline Malignancies of Breast, Ovary, and Mesothelial Cells’’; ‘‘Borderline Malignancies of Liver, Stomach, and Large Bowel’’; and a Special Session on ‘‘From Sample to Molecular Genetics: Applications of Microarray Technology to the Study of Cancer,’’ presented by P. Fortina, MD, L. Kricka, PhD, and C. Stoeckert, PhD. A limited number of abstracts will be selected for poster presentations on one of the specific subjects of the plenary session. Official Languages: English and Italian For further information please contact: Omega Congress, Piazza Amedeo, 14, 80121 Napoli, Italy. TEL: ⫹39.81.40.09.85; FAX: ⫹39.81.794.43.65; EMAIL: [email protected]. Pathology Update November 3-4, 2000 Women’s College Health Sciences Centre, Women’s College Site, Toronto, Ontario Study Credits: Y Maintenance of Certification Program of the Royal College of Physicians & Surgeons of Canada Y AMA Category I For further information, please contact: Continuing Education, Faculty of Medicine, University of Toronto, 150 College Street, Room 121, Toronto, Ontario M5S 3E2. TEL: (416)
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978-2719; FAX: (416) 971-2200; EMAIL: kristin.parsonson@ utoronto.ca. WEBSITE: http://www.cme.utoronto.ca. Symposium and Workshop on Infectious Diseases November 11-12, 2000 Hong Kong Organized by the Hong Kong Division of the International Academy of Pathology (HKIAP), and directed by Dr A.M. Marty, Chief of the Infectious Disease Branch, Armed Forces Institute of Pathology, Washington, DC, the course features a workshop on ‘‘Identification of Viruses, Bacteria, Fungi, and Parasites in Tissue Sections, Recognition of Their Mimickers, and Avoiding Diagnostic Pitfalls,’’ a symposium on ‘‘Pathogenesis of Malaria; Techniques for Rapid Diagnosis of Gastrointestinal Pathogens; and Infections of Emerging Importance and in the Immunocompromised Host,’’ and a seminar on un-known slides. It will be targeted to both Anatomical Pathologists and Microbiologists. For further information, please contact: the Secretary, HKIAP, Dr Tony W.H. Shek, Department of Pathology, Queen Mary Hospital, Hong Kong. FAX: ⫹852-2872-8098; EMAIL: [email protected]. First Annual Meeting of the Ibero-Latinamerican Society of Dermatopathology November 3-4, 2000 Vin ˜ a del Mar, Chile Official languages: Spanish and Portuguese. Major topics: cutaneous lymphoma, follicular neoplasms, bullous
dermatoses, new entities in Dermatopathology, and a self-assessment course. For further information, please contact: Sergio Gonzelez, MD, Dept. of Pathology, Dermatopathology Unit, Catholic University School of Medicine, Marcoleta 367, Santiago 6510260, Chile. TEL: (562) 686-3206; FAX: (562) 639-5101; EMAIL: [email protected]. Surgical Pathologist—Thomas Jefferson University Hospital Philadelphia, PA Thomas Jefferson University Hospital’s, Department of Pathology is seeking to recruit an experienced surgical pathologist at the level of Assistant Professor. Principal duties will be in general surgical pathology, but special competence in breast pathology, soft tissue pathology, and endocrine pathology would be desirable. Qualified candidates should be certified in anatomic pathology and have a minimum of 5 years experience in a teaching hospital environment. Thomas Jefferson University Hospital is a major teaching hospital with comprehensive programs in all major areas. Faculty is provided with ample support and time to pursue research interests and are expected to participate in departmental educational programs. TJU offers an excellent salary/benefit package. Interested applicants should respond by sending a CV and letter to Peter A. McCue, MD, Professor and Director Anatomic Pathology, 132 S. 10th Street, 263M, Philadelphia, PA 19107. TJU Hospital is an equal opportunity, affirmative action employer.
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intrathecal PNETs is important as those arising in the spinal cord develop in the central nervous system, whereas those arising in the cauda equina develop in the peripheral nervous system. The histogenesis of intrathecal PNETs may be multifactorial. HUM PATHOL 31: 999-1001. Copyright © 2000 by W.B. Saunders Company Key words: primitive neuroectodermal tumor, small round-cell tumor, neoplasm, cauda equina. Abbreviations: PNET, primitive neuroectodermal tumor; MRI, magnetic resonance imaging; H&E, hematoxylin and eosin; HPS, hematoxylin phloxine saffron; PAS, periodic-acid Schiff; EMA, epithelial membrane antigen; LCA, leukocyte common antigen; NSE, neuron-specific enolase; CNS, central nervous system.
Primitive neuroectodermal tumors (PNETs) are malignant neoplasms whose classification has been controversial since their description in 1973 by Hart and Earle.1 These tumors are composed of predominantly undifferentiated cells and in the cerebellum have been traditionally known as medulloblastomas.2,3 PNETs may also arise in the cerebrum, the brainstem, the pineal gland, the spinal cord, and peripheral nerves.1-13 Primary intraspinal PNETs are rare and can arise as intramedullary, extramedullary, or extradural tumors at any level of the spinal cord.4-5 Primary PNETs of the cauda equina are even less common.6-10 We describe the eighth reported primary PNET of the cauda equina in a 52-year-old man with no significant past medical history.
intrathecal tumor that extended from the L2-L3 disc space caudally to the inferior body of L5 (Fig 1). This tumor appeared to encase, rather than displace, the spinal nerve roots and specifically did not involve the conus medullaris. The radiological growth pattern of the tumor was highly suggestive of an ependymoma. MRI of the brain with gadolinium enhancement was normal. At surgery, a soft, friable, intrathecal tumor was confirmed underlying atrophic dura. The tumor encased the spinal nerve roots and displaced some of the roots laterally and others posteriorly. Intraoperative frozen section showed a necrotic, undifferentiated, small round-cell tumor, and a PNET was diagnosed on permanent sections. Microsurgical excision of the tumor was performed; however, tumor debulking was only possible, as the tumor was intricately associated with many of the nerve roots. The patient had an uncomplicated postoperative course, and his neurological symptoms gradually improved. After his surgical wound had healed, he received whole central nervous system irradiation with a total dose of 3,850 cGy, followed by a radiation dose of 1,750 cGy directed at the tumor. The tumor was radiosensitive, and a year after the discovery of his intrathecal neoplasm, the patient has had no clinical or radiological evidence of tumor recurrence.
CASE REPORT A 52-year-old man presented to the Ottawa General Hospital with a 6-month history of progressive back pain and difficulty in ambulating and a 2-week history of post-voiding urinary incontinence and numbness in the caudal area. Physical examination confirmed decreased sensation to pinprick in the L4-S2 distributions on the left side and in the S1-S2 distributions on the right side. The patient had markedly decreased anal sphincter tone, marked limitation of straight leg raising bilaterally, and grade 3/5 weakness of dorsiflexion in his left leg. He had diminished knee jerk reflexes bilaterally. The patient was diagnosed with an incomplete cauda equina syndrome. Emergency magnetic resonance imaging (MRI) of the spine with gadolinium enhancement showed a 10-cm long
From the Departments of Laboratory Medicine, Anatomical Pathology, Neurosurgery, Surgery, Radiology, Radiation Oncology, Medical Oncology, and Internal Medicine, Ottawa Hospital-General Campus, and University of Ottawa, Ottawa, Ontario, Canada. Address correspondence and reprint requests to Susan J. Robertson, MD, FRCPC, Anatomical Pathology, Ottawa Hospital-General Campus, 501 Smyth Road, Ottawa, Ontario, Canada K1H 8L6. Copyright © 2000 by W.B. Saunders Company 0046-8177/00/3108-0017$10.00/0 doi: 10.1053/hupa.2000.16532
MATERIALS AND METHODS Biopsy specimens were fixed in 10% buffered formalin after a representative section was submitted for frozen section. Paraffin-embedded tissue was stained with hematoxylin and eosin (H&E) and hematoxylin phloxine saffron (HPS). Periodic acid-Schiff (PAS) stains with and without diastase digestion were performed. Immunohistochemistry was performed on 4- thick deparaffinized tissue sections using an avidin-biotin horseradish peroxidase method and antibodies directed against CD20 (1:400 dilution; DAKO, Carpinteria, CA), CD45RO (1:50; DAKO), CD57 (1:50; Becton Dickinson, San Jose, CA), CD99 (1:100; DAKO), chromogranin (1:500; Biogenix, San Ramon, CA), cytokeratin CAM 5.2 (1:200; Becton Dickinson, Mississauga, Canada), desmin (1:500; DAKO), epithelial membrane antigen (EMA; 1:750; DAKO), glial
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FIGURE 1. Primary primitive neuroectodermal tumor of the cauda equina. Sagittal magnetic resonance imaging scan enhanced with gadolinium showing an intrathecal tumor extending from the L2-L3 disc space caudally to the inferior body of L5. There is no involvement of the conus medullaris by tumor.
development of PNETs.1,11-12 In their examination of cerebral PNETs, Hart and Earle1 restricted their definition of PNET to tumors containing 90% to 95% undifferentiated cells. This concept of PNET was expanded by Becker and Hinton3 and Rorke2 when they proposed classifying all central nervous system (CNS) tumors with a predominant undifferentiated, primitive cell component as PNETs. This classification of PNET has been controversial, and the recent World Health Organization classification of brain tumors avoids this controversy by recommending that PNET be used as a “generic term” for cerebellar medulloblastomas and other CNS tumors that are morphologically identical to medulloblastoma.11-12 It is also well recognized that PNETs are not only restricted to the CNS but that they may also arise along peripheral nerves.3,6-10,13 PNETs are classified as small, round-cell tumors and must be distinguished from similar tumors that include extraskeletal forms of Ewing’s sarcoma, lymphoma, rhabdomyosarcoma, and small-cell carcinoma.6,9,13-15 PNETs are undifferentiated neoplasms characterized by small, uniform, round cells with hyperchromatic nuclei that show evidence of neural differentiation.6,13-15 The diagnosis of PNET is dependent on the identification of either Homer-Wright or Flexner-Wintersteiner rosettes.6,13-14 No specific criteria exist for the quality or quantity of rosettes, and some PNETs may show only
fibrillary acidic protein (GFAP; 1:750; DAKO), leukocyte common antigen (LCA; 1:400; DAKO), neurofilaments (1: 100; DAKO), neuron-specific enolase (NSE; 1:500; DAKO), S100 (1:75; DAKO), serotonin (1:100; DAKO), somatostatin (1:100; DAKO), synaptophysin (1:100; Biogenix), and vimentin (1:100; DAKO). PATHOLOGICAL FINDINGS A necrotic, undifferentiated, round-cell tumor was identified at frozen section. On permanent H&E stained sections, the tumor was characterized by small undifferentiated cells with distinct, but scant, cytoplasm and hyperchromatic nuclei that showed margination of chromatin and inconspicuous nucleoli. Undifferentiated round cells formed occasional Homer-Wright rosettes (Fig 2). No ependymal type perivascular rosettes were identified. Mitotic figures and apoptotic tumor cells were both prominent. Focal tumor cells contained glycogen, as shown by PAS-positive intracytoplasmic granules that disappeared after diastase digestion. No ganglion cells were identified. The round-cell tumor exhibited strong immunohistochemical staining for synaptophysin, CD99 (Fig 3), and vimentin and focal staining for GFAP, NSE, and S100. Immunohistochemical stains directed against CD20, CD45RO, CD57, cytokeratin CAM 5.2, chromogranin, desmin, EMA, LCA, neurofilaments, serotonin, and somatostatin were all negative. The histologic and immunohistochemical features of this undifferentiated round-cell tumor were consistent with a diagnosis of PNET. DISCUSSION PNETs are generally regarded as embryonal tumors whose histogenesis is both unknown and possibly multifactorial.1,11 PNETs are thought to arise from immature progenitor cells; however, the exact cell of origin has not been identified. Multiple histogenetic theories have been proposed for the
FIGURE 2. Photomicrograph of the primitive neuroectodermal tumor with a Homer-Wright rosette and prominent mitotic figures. (HPS stain, original magnification ⫻400.)
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tant, as the cauda equina is essentially part of the peripheral nervous system, where spinal nerve root axons have already exited the cord and have become dependent on Schwann cells for the maintenance of their myelin sheaths.9 Our patient had a PNET arising in the cauda equina that was confirmed to be primary in origin. This tumor showed evidence of neural differentiation characterized by well formed Homer-Wright rosettes and immunoreactivity for synaptophysin, NSE, S100, and GFAP. The immunohistochemical phenotype of the tumor was inconsistent with any round-cell tumor other than PNET. Tumor expression of CD99 was evidence of a PNET/Ewing family of tumors. GFAP expression by this PNET was particularly interesting, as immunoreactivity for this neural marker, along with chromogranin, is considered evidence of more mature neural differentiation.15 A previous study by Brinkhuis et al15 suggested that the use of both chromogranin and GFAP was of limited value in the diagnosis of PNETs. Our patient’s tumor did not express any immunoreactivity for chromogranin. The accurate diagnosis of PNETs is important, as these are aggressive neoplasms.4,12-13 The distinction between PNET and Ewing’s sarcoma is also important, as PNETs are thought to carry a worse prognosis.15 No standard therapy exists for spinal cord or cauda equina PNETs, although many patients have been treated with a combination of chemotherapy, radiotherapy, and surgery.4 Unfortunately, even with therapy, patient prognosis is poor and survival beyond 2 years is rare. Our patient continues to be followed closely for evidence of tumor recurrence. Acknowledgment. We would like to thank Dr L. E. Becker of The Hospital for Sick Children’s Department of Pathology, Toronto, Canada, for his review of this case.
REFERENCES
FIGURE 3. Primitive neuroectodermal tumor cells expressing strong immunoreactivity for the surface glycoprotein CD99. (Immunohistochemical stain for CD99, original magnification ⫻600.)
abortive rosette forms.6,14 Other diagnostic features of PNETs include the rare identification of ganglion cells, reactivity for 2 or more neural immunohistochemical markers, and ultrastructural evidence of neural differentiation.6,13-15 Peripheral PNETs and Ewing’s sarcomas are thought to be closely related tumors, as they have the same reciprocal chromosomal translocation t(11;22)(q24:q12), similar tumor expression of the glycoprotein CD99, and they share expression of the same oncogenes, including c-myc, c-myb, c-ets-1, and N-myc.6,14-15 Evidence of neural differentiation in PNETs is the phenotypic feature that differentiates these tumors from Ewing’s sarcoma.14-15 Although PNETs are common in the pediatric population, occurring primarily as cerebellar medulloblastomas, PNETs are rare in adults, especially presenting as spinal cord or cauda equina tumors.3-10,12-13 The majority of PNETs that involve the cord or the spinal nerve roots are metastatic in origin and are the result of “drop” metastases from tumors more superior in the neruroaxis.4,9 Any intraspinal PNET must be considered a metastatic tumor until proven otherwise.7 Only 14 primary PNETs of the spinal cord and 7 primary PNETs of the cauda equina have been described previously.4-10 The distinction between these 2 sites is impor-
1. Hart MN, Earle KM: Primitive neuroectodermal tumors of the brain in children. Cancer 32:890-897, 1973 2. Rorke LB: The cerebellar medulloblastoma and its relationship to primitive neuroectodermal tumors. J Neuropathol Exp Neurol 42:1-15, 1983 3. Becker LE, Hinton D: Primitive neuroectodermal tumors of the central nervous system. HUM PATHOL 14:538-550, 1983 4. Deme S, Ang L-C, Skaf G, et al: Primary intramedullary primitive neuroectodermal tumor of the spinal cord: Case report and review of the literature. Neurosurgery 41:1417-1420, 1997 5. Papadatos D, Albrecht S, Mohr G, et al: Exophytic primitive neuroectodermal tumor of the spinal cord. Am J Neuroradiol 19:787-789, 1998 6. Hisaoka M, Hashimoto H, Murao T: Peripheral primitive neuroectodermal tumour with ganglioneuroma-like areas arising in the cauda equina. Virchows Arch 431:365-369, 1997 7. McDermott VGM, El-Jabbour JN, Sellar RJ, et al: Primitive neuroectodermal tumour of the cauda equina. Neuroradiology 36:228-230, 1994 8. Liu H-M, Yang WC, Garcia RL, et al: Intraspinal primitive neuroectodermal tumor arising from the sacral spinal nerve root. J Comput Tomogr 11:350-354, 1987 9. Kepes JJ, Belton K, Roessman U, et al: Primitive neuroectodermal tumors of the cauda equina in adults with no detectable primary intracranial neoplasm—three case studies. Clin Neuropathol 4:1-11, 1985 10. Smith DR, Hardman JM, Earle KM: Metastasizing neuroectodermal tumors of the central nervous system. J Neurosurg 31:50-58, 1969 11. Kleihues P, Burger PC, Scheithauer BW: The new WHO classification of brain tumours. Brain Pathol 3:255-268, 1993 12. Lantos PL, VandenBerg SR, Kleihues P: Tumours of the nervous system, in Graham DI, Lantos PL (eds): Greenfield’s Neuropathology. London, Arnold, 1997, pp 583-879 13. Enzinger FM, Weiss SW: Primitive neuroectodermal tumors and related lesions, in Enzinger FM, Weiss SW (eds): Soft Tissue Tumors. St Louis, Mosby, 1995, pp 929-964 14. Dehner LP: Primitive neuroectodermal tumor and Ewing’s sarcoma. Am J Surg Pathol 17:1-13, 1993 15. Brinkhuis M, Wijnaendts LCD, van der Linden JC, et al: Peripheral primitive neuroectodermal tumour and extra-osseous Ewing’s sarcoma: A histological, immunohistochemical and DNA flow cytometric study. Virchows Arch 425:611-616, 1995
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SUDDEN CARDIAC DEATH OWING TO PSEUDOXANTHOMA ELASTICUM: A CASE REPORT KURT B. NOLTE, MD A 26-year-old woman collapsed and died suddenly while dancing. Autopsy findings included the cutaneous lesions of pseudoxanthoma elasticum (PXE), a rare genetic disease with autosomal dominant and recessive inheritance patterns. Pathologic findings of PXE (degenerated elastic fibers) were seen in the stenotic epicardial coronary arteries, the intramyocardial arterioles, the subendocardium, the mitral valve, and the blood vessels of other viscera. The mitral valve was slightly myxoid. Intramyocardial arteriolar involvement has not been previously described in PXE. The other cardiac findings have only been described in a few cases. Although mitral valve prolapse in PXE has been shown echocardiographically, it is unclear whether or not
the mitral valve findings in this case represent the substrate for this condition. It is important that autopsy pathologists search carefully for the pathognomonic skin lesions of PXE in cases of sudden death associated with coronary disease, mitral valve prolapse, or endocardial lesions. Recognition of this disease is essential for proper genetic counseling of surviving family members. HUM PATHOL 31:1002-1004. Copyright © 2000 by W.B. Saunders Company Key words: pathology, pathophysiology, forensic science, pseudoxanthoma elasticum, mortality, autopsy, cardiac disease. Abbreviations: PXE, pseudoxanthoma elasticum; LAD, left anterior descending; LCX, left circumflex.
Pseudoxanthoma elasticum (PXE) is a rare, inherited, systemic disease of elastic tissue that especially affects the skin, eyes, and cardiovascular system. The prevalence of the disease is estimated at 1 in 100,000 population, about the same frequency as Marfan’s syndrome. No racial or geographic predominance has emerged. PXE is inherited through both autosomal recessive (90%) and autosomal dominant (10%) patterns. There is no known genetic marker. The pathologic feature of this disease is central calcification and fragmentation of fully developed elastic fibers. The primary defect and pathogenesis are unknown but may include the synthesis of abnormal elastic fibers which subsequently calcify; and the alteration of normal elastic fibers by acid mucopolysaccharides, proteases or other substances resulting in calcification.1 Although the cutaneous and ocular pathology of PXE is well described, only a few autopsy cases with cardiac involvement are reported. These cases have changes in the coronary arteries, endocardium, valves, and conducting system.2-11 Corresponding clinical manifestations of PXE include angina, congestive heart failure, and mitral valve prolapse.12-14 This report describes a case of sudden death owing to cardiac involvement by PXE and details the pathologic findings.
normal appearing collagen bundles. This material stained positively for elastic tissue with a Verhoeff-van Gieson stain and for calcium with a Von Kossa stain. The heart weighed 220 g. The coronary arteries were normally distributed with a dominant right coronary artery. All of the epicardial coronary arteries were of small caliber and were concentrically narrowed. The right and the left main coronary arteries had an external diameter of 4 mm and a luminal diameter of 2 mm. The left anterior descending (LAD) branch had an external diameter of 4 mm and a proximal luminal diameter of 2 mm. At 1.5 cm from the origin, the LAD tapered to a pinpoint lumen (narrowed by greater than 95% cross sectional area). The left circumflex (LCX) branch had an external diameter of 2 mm and a proximal luminal diameter of 1 mm. At 1.5 cm from the origin, the LCX also tapered to a pinpoint lumen (narrowed by greater than 95% cross sectional area). The intima of these vessels appeared focally yellow and myxoid. There were focal yellow-white endocardial streaks in the right atrium (Fig 1). The tricuspid, pulmonic, and aortic valves were normal. The mitral valve showed slightly myxoid leaflets with moderate interchordal hooding. The chordae tendineae appeared normal. The myocardium was dark brown and without ischemic change. The aorta showed a few yellow intimal streaks. Microscopic sections of the coronary arteries, the left anterior descending coronary vein, and the renal and adrenal arterioles showed myxoid intimal fibrosis and fragmentation of the elastica with degenerated, calcified fibers identical to
CASE REPORT A 26-year-old woman collapsed suddenly while dancing. An electrocardiogram showed ventricular fibrillation. Resuscitation efforts were unsuccessful. Autopsy findings included confluent yellow papules and plaques with a “chicken skin” appearance over the anterior and posterior neck, throughout the inguinal regions, in the antecubital fossae, and around the umbilicus. Microscopic sections of the skin lesions showed basophilic granular material in the middle and deep dermis interspersed between
From the Office of the Medical Investigator, University of New Mexico School of Medicine, Albuquerque, NM; and Medical Examiner/Coroner Information Sharing Program, Surveillance and Programs Branch, Division of Environmental Hazards and Health Effects, National Center for Environmental Health, Centers for Disease Control and Prevention, Atlanta, GA. Presented at the 23rd Annual Meeting, National Association of Medical Examiners, Sanibel Island, FL, 1989. Address correspondence and reprint requests to Kurt B. Nolte, MD, Office of the Medical Investigator, University of New Mexico School of Medicine, Albuquerque, NM 87131-5091. Copyright © 2000 by W.B. Saunders Company 0046-8177/00/3108-$10.00/0 doi: 10.1053/hupa.
FIGURE 1.
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the elastic fibers of the skin lesions (Figs 2A, B). No lipid deposits were present. Similar collections of degenerated elastic fibers were seen in the subendocardium of the right atrium, left atrium, and left ventricle (Fig 3) and were widespread within the mitral valve. The elastic laminae of intramyocardial arterioles were extensively calcified and fragmented without intimal changes. Adjacent to the His bundle and left bundle branch fibers were focal calcifications. The aorta showed focally fragmented calcified elastic fibers within the media. The remainder of the viscera was unremarkable. The cause of death was listed as “cardiac ischemia due to abnormal coronary arteries due to pseudoxanthoma elasticum.” A subsequent discussion with the decedent’s husband showed that PXE had been previously diagnosed in both the decedent and her sister. In this family, the disease was thought to follow an autosomal recessive inheritance pattern. DISCUSSION Coronary involvement by PXE has potentially lethal consequences. In 2 large clinical series, 13% and 52% of PXE patients had angina pectoris.1,5 Coronary pathology similar to that noted in this case is likely the underlying cause of the angina pectoris often present in these patients. Of 17 postmortem PXE hearts described in the English language liter-
FIGURE 3. Collection of degenerated elastic fibers in the atrial subendocardium. (Verhoeff-van Gieson stain, original magnification 100⫻.)
FIGURE 2. Left anterior descending coronary artery with (A) myxoid intimal fibrosis and fragmented, calcified, elastic lamina (hematoxylin and eosin stain, original magnification 100⫻) and (B) degenerated elastic fibers indicated by arrows (Verhoeff-van Gieson stain, original magnification 400⫻).
ature, 13 (76%) had some degree of coronary “atherosclerosis” or calcification.2-11 Two of the 13 cases had a calcified and fragmented coronary elastica similar to the lesions identified in this report.7,10 Pathologic segments of coronary artery removed during bypass grafting from 2 young women with PXE and angina showed similar changes, with a calcified internal elastic lamina in 1 case12 and disrupted elastic laminae, myxoid subendothelial thickening, and medial fibrosis in the other case.15 The presence of these histologic findings, especially in very young individuals, and the absence of lipids from the lesions suggest PXE of the coronary arteries rather than early atherosclerosis. Degeneration of blood vessels in PXE is probably a generalized process as up to 45% of patients with the disease have claudication.1,5 In the present case, PXE degeneration was evident in adrenal and renal arterioles, aorta, and a coronary vein, in addition to the coronary arteries. Mitral valve prolapse has been identified by echocardiogram in 71% of patients with PXE.13 Calcified or thickened valves are described in 4 other cases, but details are lacking.4,5,8 The case described here had an abnormal mitral valve with disrupted elastic fibers. Whether or not this is the substrate for mitral valve prolapse in PXE is unknown. Endocardial lesions similar to those seen in this case have been shown in 8 other cases,4-6,8-10 including 1 case where the bundle
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branches were encased in the thickened endocardium.10 Endocardial PXE can lead to restrictive cardiomyopathy.6 Congestive heart failure is frequently described in PXE and is a potential consequence of ischemic, valvular, or restrictive endocardial disease.6-10,12 As seen in this case, another possible etiology of both congestive failure and angina in PXE is cardiac intramural arteriolar degeneration. Although this condition has not been previously described pathologically, intramural coronary artery involvement was suspected clinically as the cause of angina and congestive failure in a PXE patient with angiographically normal epicardial vessels and fragmented endocardial elastica on biopsy.14 This case illustrates that sudden death owing to cardiac PXE has a range of potential pathophysiological mechanisms. Fatal arrhythmias may be owing to large- or small-vessel coronary stenosis with ischemia, conducting system, and endocardial disruption by degenerated elastic fibers, or mitral valve prolapse. Sudden death associated with PXE has only been described in 3 previously asymptomatic boys who collapsed during exercise.2 One boy had coronary artery changes and another boy had endocardial involvement. No autopsy was performed in the third case. Although the cutaneous lesions of PXE are of cosmetic importance, they also serve as a marker for potentially fatal cardiovascular disease, especially in young people. Therefore, it is important that autopsy pathologists search carefully for the pathognomonic skin lesions in cases of sudden death associated with coronary disease, mitral valve prolapse, or endocardial lesions. Recognition of this disease is essential for proper genetic counseling of surviving family members. Acknowledgment.
The author is grateful to James L. Luke,
MD, Ross E. Zumwalt, MD, and Bronwyn E. Wilson, MD, for editorial comments and direction. REFERENCES 1. Neldner KH: Pseudoxanthoma elasticum. Clin Dermatol 6:1-159, 1988 2. Wilhelm K, Paver K: Sudden death in pseudoxanthoma elasticum. Med J Aust 2:1363-1365, 1972 3. Hamilton-Gibbs JS: Death from coronary calcinosis occurring in the baby of a mother presenting with pseudoxanthoma elasticum. Australas J Dermatol 11:145-148, 1970 4. McKusick VA: Heritable Disorders of Connective Tissue. St Louis, MO, Mosby Co, 1972, pp 475-520 5. Carlborg U, Ejrup B, Gronblad E, et al: Vascular studies in pseudoxanthoma elasticum and angioid streaks. Acta Medica Scand 166:1-84, 1959 6. Navarro-Lopez F, Llorian A, Ferrer-Roca O, et al: Restrictive cardiomyopathy in pseudoxanthoma elasticum. Chest 78:113-115, 1980 7. Perrot LJ, Mrak RE: Cardiac involvement in a child with unsuspected pseudoxanthoma elasticum. Pediatr Pathol 13:273-279, 1993 8. Coffman JD, Sommers SC: Familial pseudoxanthoma elasticum and valvular heart disease. Circulation 19:242-250, 1959 9. Mendelsohn G, Bulkley BH, Hutchins GM: Cardiovascular manifestations of Pseudoxanthoma elasticum. Arch Pathol Lab Med 102:298-302, 1978 10. Huang S, Kumar G, Steele HD, et al: Cardiac involvement in pseudoxanthoma elasticum. Report of a case. Am Heart J 74:680-686, 1967 11. Milstoc M: An unusual anatomo-pathologic aspect of a case with pseudoxanthoma elasticum. Dis Chest 55:431-434, 1969 12. Lebwohl M, Halperin J, Phelps RG: Brief report: Occult pseudoxanthoma elasticum in patients with premature cardiovascular disease [see comments]. N Engl J Med 329:1237-1239, 1993 13. Lebwohl MG, Distefano D, Prioleau PG, et al: Pseudoxanthoma elasticum and mitral-valve prolapse. N Engl J Med 307:228-231, 1982 14. Przybojewski JZ, Maritz F, Tiedt FA, et al: Pseudoxanthoma elasticum with cardiac involvement. A case report and review of the literature. S Afr Med J 59:268-275, 1981 15. Bete JM, Banas JS, Jr, Moran J, et al: Coronary artery disease in an 18-year-old with pseudoxanthoma elasticum: Successful surgical therapy. Am J Cardiol 36:515-520, 1975
BOOK REVIEWS Pathology for the Health-Related Professions (ed 2). Ivan Damjanov. Philadelphia, PA, W.B. Saunders Company, 2000, 545 pages, $52.00. A key element in the education of allied health professionals is the development of an understanding of the disease process. Professors engaged in the teaching of pathology to this group of students have long struggled with the need for a textbook directed specifically at this audience. While many textbooks purport to be designed for this purpose, an examination of their contents generally shows them to be insufficient in some manner. Some are digests of larger, more detailed texts, and as such, do not read well. Others turn out to be mere surveys of human disease and do not allow the student to develop an understanding of the pathophysiologic processes involved. Yet another group delves too deeply into pathophysiology, leaving undergraduate allied health students gasping and frustrated. Publication of the first edition of Pathology for the HealthRelated Professions by Ivan Damjanov in 1996 filled the need for a textbook written for this specific audience. Although an excellent text, as with most first editions, there were areas which could be improved. Examination of the recently published second edition of this text shows that attention has been paid to the suggestions undoubtedly made by faculty
and students using this resource. Thankfully, the underlying character of the text has been maintained and enhanced. The author’s obvious enthusiasm for his subject is conveyed in a manner which encourages the reader and promotes a desire for understanding of the subject. Our best students will invest their time in reading even the driest of textbooks, and they are not a difficult group to teach. It is the next tier of students, those who have ability but lack motivation, that are the greatest challenge to textbook authors and classroom professors. For those students, a book must not merely contain the required information, it must be presented in a highly accessible manner. It is a further benefit if the text is somewhat entertaining. The author accomplishes this feat in Pathology for the Health-Related Professions. Damjanov has the ability to describe pathologic processes as one would tell a story, encouraging the student to continue reading beyond merely the assigned topic or pages. Of particular help in this regard are sidebars contained in boxes entitled “Did you know?” which place the topic under discussion in historical or popular context. I have observed students thumbing through specifically looking for these boxes and the information they contain. As in the first edition, this book begins with a review of cell biology and discussion of cell pathology. One can not begin to understand the disease process until an understanding of the cell is accomplished. Without this foundation,
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organs are merely “black boxes” in which magic happens (or, in the case of disease, goes awry). The author has further illuminated his discussion of this topic by making the illustrations in this section more colorful and appealing. In fact, one of the main improvements in the second edition is the addition of color to many of the previously black and white or half-tone illustrations. This seemingly minor change tends to draw the readers’ eye and deliver the information with remarkable clarity. A common misconception among textbook writers and perhaps among educators is that photomicrographs are the most efficient way of showing histopathology. In fact, I have often observed students struggling with photomicrographs of structures which could be more clearly conveyed by illustrations. I have frequently resorted to drawing the structure in question, to help the student understand the photomicrograph. In the second edition of Pathology for the Health-Related Professions, the author has replaced several problematic photomicrographs with illustrations. This again is a notable improvement. Subsequent chapters deal with Inflammation, Immunopathology, Neoplasia, Genetic and Developmental Diseases, Fluid, and Hemodynamic Disorders. Later chapters follow a systemic approach to disease and apply the basics learned in the earlier chapters. As each disease is presented, a brief introductory discussion leads to topics such as Etiology and Epidemiology, Pathogenesis, Clinical Presentation, Pathologic Findings, and Treatment. This enables the student to quickly find the information needed. This ease of use is further aided by the listing of Learning Objectives, and Additional Key Terms and Concepts at the beginning of each chapter. While this text aptly fills the needs of students of the allied health professions, its ease of presentation and colorful illustrations make it a valuable resource to many in the medical community.—ROBERT K. CLARK, PHD, Associate Professor, Division of Health and Sciences, Cumberland County College, Vineland, NJ. Bone and Soft Tissue Tumors. Mario Campanacci. Wien, NY, Springer-Verlag, 1999, 1,319 pages. The second edition of the late Dr Campanacci’s book represents an almost entirely new book rather than an update of the first edition. As stated in the Preface, the book has been rewritten in English (as opposed to the first edition which was translated from Italian) and incorporates a number of new illustrations, the most noticeable of which are updated magnetic resonance images. These changes have resulted in a wonderfully written, almost encyclopedic text on bone and soft tissue tumors. The book is divided into 3 segments. The first is an introduction to general concepts, including terminology, radiographic principles, grading and staging, surgical margins, and treatment. The information provided on surgical mar-
gins and the Enneking/Musculoskeletal Tumor Society staging system is particularly useful for pathologists not familiar with these concepts. The second segment, which accounts for approximately two thirds of the book, is devoted to tumors and tumor-like lesions of bone. Dr Campanacci’s experience and the wealth of material available at the Rizolli Institute are quite evident, as virtually all entities known to occur in bone are covered. The discussion of each individual lesion begins with a definition of the entity followed by detailed information regarding epidemiology and location, including figures depicting the Rizolli Institute’s experience with the tumor in question. Next, clinical information, radiographic features, and gross and histopathologic findings are presented, each complemented by a wealth of black and white photographs. For pathologists not experienced in interpretation of radiographic studies, the book offers numerous examples and variations of the radiologic features of each entity. Each chapter is completed with a detailed discussion of differential diagnosis, treatment, and prognosis. Several chapters are particularly informative, including those on osteofibrous dysplasia and adamantinoma, and those devoted to central and surface osteosarcomas. The third segment of the book covers tumors and tumorlike conditions of soft tissue. While most tumors and tumorlike conditions are presented, they are not covered nor illustrated in the depth of the osseous lesions. Nonetheless, sufficient information is provided on differential diagnosis and immunohistochemical staining to make these chapters useful to surgical pathologists. Furthermore, few texts are available which incorporate both bone and soft tissue lesions in a single volume. The criticisms of the book are minor and few in number. Although this book is copyrighted 1999, the majority of the references are from 1997 or earlier, with only a handful of citations from 1998. Nonetheless, most of the “classic” references for any given tumor are listed. Second, all of the photomicrographs and gross photographs are in black and white. While the illustrations are of excellent quality overall, most readers now expect color photographs, particularly given the cost of the book. Finally, although the book has been rewritten in English, there remain words and phrases which still require some clarification. These criticisms are minor and detract little from the overall excellent quality of the book. In summary, the second edition of Dr Campanacci’s book is well written and well illustrated and is a text which any surgical pathologist would find useful when faced with one of these relatively uncommon lesions, particularly those arising in bone.—JOHN D. REITH, MD, Assistant Professor, Departments of Pathology, Immunology and Laboratory Medicine and Orthopaedic Surgery, University of Florida College of Medicine, Gainesville, FL. JOHN R. GOLDBLUM, MD, Department of Anatomic Pathology, The Cleveland Clinic Foundation, Cleveland, OH.
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CORRESPONDENCE On Tiny Tissue Samples, Common Sense, and Molecular Pathology To the Editor:—For tissue-based diagnosis of disease, pathologists often have to rely on increasingly small samples. However, the following case illustrates that this is not entirely risk free. A dysplastic fragment of epithelium was seen in the endoscopic biopsy tissue of a whitish lesion in the lower esophagus from a 46-year-old woman. Consequently, the patient was kept under close surveillance. However, 4 biopsies taken in the following 9 months failed to show any abnormality and the possibility of a mix-up was raised. The mix-up in the first biopsy was proven using dysplastic (D) and normal (N1), routinely H&E stained tissue fragments (Fig 1A) scraped from the same glass slide manually with a scalpel under microscopic examination and normal tissue (N2) from a biopsy 9 months later. From these minuscule tissue fragments, DNA was extracted, and allelotyping was performed by radioactive polymerase chain reaction (PCR) of polymorphic microsatellites using 4 markers.1,2 PCR, followed
by size separation of the products was performed as described earlier.1 Biopsy specimen mix-ups can occur in many ways and many places, especially when such small biopsies are involved. One possibility is shown in Figure 1B, although it is standard procedure in our laboratory to additionally use specially designed bags with small “lumina” for processing small tissue fragments. The usefulness of molecular biological techniques to sort out mix-ups has been shown in other papers.3 In this case, we show that even from a single routinely processed and stained tissue section, sufficient DNA can be retrieved for PCR amplification, thus allowing an unequivocal conclusion. The procedure is very simple, and results can be obtained in 2 or 3 days, making this test useful whenever doubt arises with respect to the identification of the patient. We used radioactive PCR for our marker analysis, but this genotyping can also be performed with fluorochrome labeled primers (eg, Perkin Elmer amplitype amplification and typing kit; PE Applied Biosystems, Foster City, CA) making this test more applicable for routine diagnostic pathology laboratories. In addition, this case illustrates the importance of keeping an open eye with respect to the possibility of a mix-up when apparent discrepancies between histology and clinical impression, or between subsequent histological findings, occur. Despite the implementation of strict quality assurance protocols, the human factor, but also the “machine factor,” can never be absolutely 100% perfect. Acknowledgment. Mr F.L. van der Panne is acknowledged for making Figure 1B.
FIGURE 1. The left part (A) shows the autoradiographic result of the polymorphic microsatellite marker (CA repeat) D8S136. The results for the other 3 (CAGrepHAR, the human androgen receptor CAG repeat [1], the CA repeats D9S161, and TP53CA [2]), were the same. The PCR product from the dysplastic tissue DNA (lane D) was found to differ from the PCR products from the two normal tissue-derived DNA samples (lanes N1 and N2). This provides conclusive evidence that the dysplastic tissue and the normal tissue fragments are derived from 2 different patients. Both normal DNA samples have the same allelotype with these 4 markers indicating with a very high likelihood that they are derived from the same patient. The right part (B) shows the fragment of dysplastic epithelium on the glass slide (center), covered for comparison with the cover lid of the standard processing container. The diameter of the holes allowing the exchange of chemicals during routine automatic overnight tissue processing is 2 mm.
K.H. LAM, MD, PHD W.J. MOOI, MD, PHD H.F.B.M. SLEDDENS, BSC W.N.M. DINJENS, MSC, PHD Department of Pathology Josephine Nefkens Institute Erasmus University Medical Center Rotterdam Rotterdam, The Netherlands 1. Sleddens HFBM, Oostra BA, Brinkmann AO, et al: Tri-nucleotide repeat polymorphism in the androgen receptor gene (AR). Nucleic Acids Res 20:1427, 1992 2. Jones MH, Nakamura Y: Detection of loss of heterozygosity at the human TP53 locus using a dinucleotide repeat polymorphism. Genes Chromosomes Cancer 5:89-90, 1992 3. O’Brian DS, Sheils O, McElwaine, et al: Sorting out mix-ups: The provenance of tissue sections may be confirmed by PCR using microsatellite markers. Am J Clin Pathol 106:758-764, 1996
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NOTICES
NOTICES The 15th Combined Skin Pathology Course September 7-12, 2000 UMD-New Jersey Medical School, Newark, NJ Under the direction of W. Clark Lambert, MD, PhD, Wayne C. Johnson, MD, Thomas D. Griffin, MD, and Alan R. Silverman, MD. This is an intensive, comprehensive course including 4 full days and 2 partial days of lectures plus presentation of over 600 selected ‘‘known’’ and ‘‘unknown’’ microscopic slides for individual study on 200 single-head binocular microscopes. Faculty for this year’s course include Dr James H. Graham, Dr Martin Munro Black, St. John’s Institute of Dermatology, St. Thomas’ Hospital, London, UK; Dr. Martin C. Mihm, Jr, Massachusetts General Hospital, Harvard Medical School, Boston, MA; and Dr Mark R. Wick, University of Virginia, Charlottesville, VA. Tuition (including full meal service and all transportation for the duration of the course) is $925 ($625 for physicians in training). Registrations are limited; slightly higher rates will apply after September 1 if space is still available. A block of hotel rooms has been reserved at a reduced rate. For further information, please contact: UMDNJ-Center for Continuing Education (Attn: Ms. Catherine Stefanelli), P.O. Box 573, Newark, NJ 07101-0573; FAX: (973) 972-7128; TEL: (800) 227-4852 or (973) 972-4267. 21st Symposium of the International Society of Dermatopathology September 14-16, 2000 Graz, Austria The 21st Symposium of the International Society of Dermatopathology will be held in Graz, Austria, on September 14-16, 2000. The focus of the Meeting will be on ‘‘Differential Diagnosis of Benign and Malignant Tumors of the Skin.’’ In addition to formal lectures, free communications, and posters, there will be a ‘‘Self-Assessment Course in Dermatopathology of Cutaneous Tumors’’ conducted by an international faculty of experts in the field. One of the main topics of the Meeting will be a ‘‘Tutorial on Melanocytic Lesions’’ consisting of 100 melanocytic tumors representing difficult cases or cases with special teaching value, to which each registrant can participate submitting one or more cases. For further information, please contact: Lorenzo Cerroni, MD, Department of Dermatology, University of Graz, Auenbruggerplatz 8, A-8036 Graz, Austria. TEL: ⫹43-316-385-2371; FAX: ⫹43316-385-2466; EMAIL: [email protected]. 9th Dermatopathology Self-Assessment Workshop September 15-16, 2000 Catholic University Medical School (Istituti Biologici), Largo F. Vito, Rome, Italy Lecturers: (C.D.M. Fletcher (Harvard University, Boston, MA), R.L. Barnhill (Pathology Services, Boston, MA). Forty cases of connective tissue neoplasms and 40 cases of melanocytic skin neoplasms will be provided and illustrated respectively by Prof. Fletcher and Prof. Barnhill. During the meeting and the days before, histological slides of all cases will be available for hands-on educational sessions at the microscope. The meeting will be the occasion for short updatings about a few newly described mesenchimal and melanocytic neoplasms of the skin.
Official Language: English Cost: $200.00. For further information, please contact: Guido Massi, MD, Department of Pathology, Catholic University Medical School, Largo F. Vito, 1-00168 Rome, Italy. TEL: ⫹39-06-305-2345, 350-3481; FAX: ⫹39-06-305-1343. EMAIL: [email protected]. 3rd Teupitz Colloquium: ‘‘Basic Research in Endocrine Dermatology’’ September 17-20, 2000 Teupitz Castle Hotel (near Berlin, Germany) For further information, please contact: Prof. Dr. Ch. C. Zouboulis, Department of Dermatology, University Medical Center Benjamin Franklin, The Free University of Berlin, Hindenburgdamm 30, 12200 Berlin, Germany. TEL: ⫹4930-84 45 28 08; FAX: ⫹49-30-84 45 42 62; EMAIL: [email protected]. 2nd Joint International Workshop: ‘‘Histologic and Cytologic Characterization of Human Tumors: Borderline Neoplasia’’ September 27-30, 2000 Hotel La Palma, Capri, Italy Workshop Chairpersons: Marluce Bibbo, MD, ScD, FIAC; Giovan Giacomo Giordano, MD, PhD; and Pietro Micheli, MD, PhD Scientific Secretary: Giulia Giordano, MD, PhD. TEL: ⫹39.081.575.06.33; FAX: ⫹39.081.575.05.10; EMAIL: [email protected]. Lecturers include: J. Rosai, MD; E. Solcia, MD; A. Carbone, MD; H. Battifora, MD; M. Bibbo, MD; J.L. Connelly, MD; C. Fenoglio-Preiser, MD; F. Gorstein, MD; R. Kurman, MD; E. Rubin, MD; R. Rubin, MD; P. Tosi, MD; A. Giordano, MD Program: Plenary sessions and slide seminars on ‘‘Borderline Malignancies of Cervix, Endometrium’’; ‘‘Atypical Cells of Undetermined Significance in Pap Smears’’; ‘‘Borderline Malignancies of Breast, Ovary, and Mesothelial Cells’’; ‘‘Borderline Malignancies of Liver, Stomach, and Large Bowel’’; and a Special Session on ‘‘From Sample to Molecular Genetics: Applications of Microarray Technology to the Study of Cancer,’’ presented by P. Fortina, MD, L. Kricka, PhD, and C. Stoeckert, PhD. A limited number of abstracts will be selected for poster presentations on one of the specific subjects of the plenary session. Official Languages: English and Italian For further information please contact: Omega Congress, Piazza Amedeo, 14, 80121 Napoli, Italy. TEL: ⫹39.81.40.09.85; FAX: ⫹39.81.794.43.65; EMAIL: [email protected]. Pathology Update November 3-4, 2000 Women’s College Health Sciences Centre, Women’s College Site, Toronto, Ontario Study Credits: Y Maintenance of Certification Program of the Royal College of Physicians & Surgeons of Canada Y AMA Category I For further information, please contact: Continuing Education, Faculty of Medicine, University of Toronto, 150 College Street, Room 121, Toronto, Ontario M5S 3E2. TEL: (416)
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978-2719; FAX: (416) 971-2200; EMAIL: kristin.parsonson@ utoronto.ca. WEBSITE: http://www.cme.utoronto.ca. Symposium and Workshop on Infectious Diseases November 11-12, 2000 Hong Kong Organized by the Hong Kong Division of the International Academy of Pathology (HKIAP), and directed by Dr A.M. Marty, Chief of the Infectious Disease Branch, Armed Forces Institute of Pathology, Washington, DC, the course features a workshop on ‘‘Identification of Viruses, Bacteria, Fungi, and Parasites in Tissue Sections, Recognition of Their Mimickers, and Avoiding Diagnostic Pitfalls,’’ a symposium on ‘‘Pathogenesis of Malaria; Techniques for Rapid Diagnosis of Gastrointestinal Pathogens; and Infections of Emerging Importance and in the Immunocompromised Host,’’ and a seminar on un-known slides. It will be targeted to both Anatomical Pathologists and Microbiologists. For further information, please contact: the Secretary, HKIAP, Dr Tony W.H. Shek, Department of Pathology, Queen Mary Hospital, Hong Kong. FAX: ⫹852-2872-8098; EMAIL: [email protected]. First Annual Meeting of the Ibero-Latinamerican Society of Dermatopathology November 3-4, 2000 Vin ˜ a del Mar, Chile Official languages: Spanish and Portuguese. Major topics: cutaneous lymphoma, follicular neoplasms, bullous
dermatoses, new entities in Dermatopathology, and a self-assessment course. For further information, please contact: Sergio Gonzelez, MD, Dept. of Pathology, Dermatopathology Unit, Catholic University School of Medicine, Marcoleta 367, Santiago 6510260, Chile. TEL: (562) 686-3206; FAX: (562) 639-5101; EMAIL: [email protected]. Surgical Pathologist—Thomas Jefferson University Hospital Philadelphia, PA Thomas Jefferson University Hospital’s, Department of Pathology is seeking to recruit an experienced surgical pathologist at the level of Assistant Professor. Principal duties will be in general surgical pathology, but special competence in breast pathology, soft tissue pathology, and endocrine pathology would be desirable. Qualified candidates should be certified in anatomic pathology and have a minimum of 5 years experience in a teaching hospital environment. Thomas Jefferson University Hospital is a major teaching hospital with comprehensive programs in all major areas. Faculty is provided with ample support and time to pursue research interests and are expected to participate in departmental educational programs. TJU offers an excellent salary/benefit package. Interested applicants should respond by sending a CV and letter to Peter A. McCue, MD, Professor and Director Anatomic Pathology, 132 S. 10th Street, 263M, Philadelphia, PA 19107. TJU Hospital is an equal opportunity, affirmative action employer.
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