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Ganglioneuromatous paraganglioma of the cauda equina—a pathological case study
Human Pathology (2005) 36, 444 – 446
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Ganglioneuromatous paraganglioma of the cauda equina—a pathological case study Peter Pytel MD, Thomas Krausz MD, FRCPath, Robert Wollmann MD, PhD, Manuel F. Utset MD, PhD* Department of Pathology, University of Chicago Hospitals, Chicago, IL 60637, USA Received 22 December 2004; revised 13 January 2005
Keywords: Divergent differentiation; Neural crest; Cytokeratin
Summary This study presents a rare case of compound paraganglioma/ganglioneuroma with comprehensive immunohistochemical studies that reveal strong cytokeratin expression in all components. A 74 - year - old woman presented with a mass lesion of the cauda equina. The 1.8 - cm tumor showed 3 histomorphologically and immunohistochemically distinct components: typical paragangliomatous neuroendocrine areas, mature ganglion cell-like neuronal areas, and a bneuromatousQ proliferation of Schwann cells with admixed axons. As often seen in cauda equina paragangliomas, the neuroendocrine cells were cytokeratin-positive. In addition, immunoreactivity for cytokeratins was also observed in the neurons and axons. This tumor illustrates the broad spectrum of divergent differentiation that can be seen in cells of sympathoadrenal lineage. D 2005 Elsevier Inc. All rights reserved.
1. Introduction Paragangliomas and pheochromocytomas are related neoplasms that are derived from neural crest cells. Paragangliomas occur in many different locations. In general, paragangliomas are regarded as low-grade tumors, but their prognosis varies depending on the site of origin. Histological features such as necrosis, high mitotic activity, coarse nodularity, and high proliferative index based on immunostaining with the monoclonal antibody (MAb) MIB1 may also correlate with biologic behavior [1,2]. The first report of a paraganglioma of the cauda equina was published in 1972 [3]. Since then, a number of case
T Corresponding author. E-mail address: [email protected] (M.F. Utset). 0046-8177/$ – see front matter D 2005 Elsevier Inc. All rights reserved. doi:10.1016/j.humpath.2005.01.024
reports and 2 larger studies of 31 cauda equina paragangliomas and of 30 spinal paragangliomas have been published [4,5]. These tumors show a slight male preponderance and a wide age distribution (13 -71 years, median approximately 50 years). Patients often present with lower back pain and leg pain, urinary and fecal incontinence, as well as sensory and motor deficits of the lower extremities. Imaging studies typically demonstrate a well-delineated mass lesion. In the cauda equina, the preoperative differential diagnosis includes ependymoma, meningioma, nerve -sheath tumors, and metastatic lesions. The pathology of cauda equina paragangliomas differs from those occurring in other locations in 2 features: (1) they more commonly show ganglion cell differentiation (up to 45%) [5] and (2) they often exhibit immunoreactivity for different cytokeratins [6]. The diagnosis of paragangliomas can be complicated by the fact that these tumors sometimes exhibit areas of
Ganglioneuromatous paraganglioma
445 tumor), these have been referred to as bcompositeQ or bcompoundQ tumors. In cases of a heterologous component (eg, adrenal cortical adenoma and spindle cell sarcoma), they have been referred to as bmixed tumors of the adrenal gland.Q There are a number of reported cases of homologous composite tumors occurring in patients with neurofibromatosis type 1 [8] and multiple endocrine neoplasia type 2A [9]. We are presenting a case of a composite tumor of the cauda equina with paraganglioma and ganglioneuroma components. Ganglion cell differentiation is, as mentioned, common in cauda equina paragangliomas [5], but a true ganglioneuromatous component is very unusual. To our knowledge, this tumor represents the fourth such reported case [3,10] occurring in the cauda equina, and this is the first report that includes immunohistochemical studies.
2. Case report
Fig. 1 Histomorphological findings. A, Mixed tumor with paraganglioma like neuroendocrine areas, peripheral nerve type Schwannian tissue, and ganglion cells. B, Paraganglioma component. C, Schwannian component with scattered ganglion cells. D, Mature ganglion cells. E, The cytokeratins demonstrate staining in the neuroendocrine cells as well as in ganglion cells and axons (Cam5.2 shown). F, Neurofilament staining highlighting the axons within the neuromatous component.
divergent differentiation [2,7]. There are a number of reports of paragangliomas and more commonly of pheochromocytomas containing divergent elements. In cases of a homologous component (eg, other neural crest derived elements such as neuroblastoma, ganglioneuroblastoma, ganglioneuroma, and malignant peripheral nerve sheath
The patient, a 74- year-old woman, presented with back and leg pain but did not have any weakness or other neurological deficits. The patient underwent surgical resection. Intraoperatively, an encapsulated tumor was observed that pushed the nerve roots of the cauda equina dorsally. The tumor was attached to a nerve root that ran within the tumor capsule. The resected specimen measured 1.8 cm and consisted of a firm nodular tumor with areas of hemorrhage. The specimen was fixed in 10% neutrally buffered formalin and embedded in paraffin. Sections were cut for hematoxylin/eosin staining as well as for immunohistochemical studies. These were performed with commercially available antibodies and according to standard protocols. Histologically, the tumor contains 3 main components (Fig. 1): It has vague cellular nodules of epithelioid cells with an organoid nested arrangement (Fig. 1B). These have the appearance of neuroendocrine cells and immunoreact with confirmatory markers (Table 1). Scattered S100positive sustentacular cells are identified within this
Table 1 Immunohistochemical staining of the neuroendocrine and neuronal components as well as of the axons and the Schwann cells of the ganglioneuromatous areas Cell type Neuroendocrine cells
Cam5.2 AE1
+++ Diffuse Ganglion cells ++/+++ Diffuse Neuromatous component: axons ++/+++ Diffuse Neuromatous component: Schwann cells
+ Focal +++ Focal ++ Focal
AE3
Syn
Chrom NF
+/++ Diffuse + Diffuse + Diffuse
++/+++ Diffuse +/++ Diffuse +/++ Diffuse
++ Focal + Focal
S100
+ Focal +/+++ Focal +++ Diffuse
GFAP MIB1 Rare positive cells (b3%)
++ Diffuse
Rare positive cells (b1%)
The staining intensity was graded as negative ( ) or as weakly, moderately, or strongly positive (+ to +++), and the distribution of the immunoreactivity was graded as bfocalQ or bdiffuse.Q Chrom indicates chromogranin; NF, neurofilament; Syn, synaptophysin. Antibody specificities: AE1, AE3, and Cam5.2; cytokeratins; Chrom, chromogranin; GFAP, glial fibrillary acidic protein; NF, neurofilament; S100, S100 protein; and Syn, synaptophysin.
446 neuroendocrine component. A component of mature ganglion cells that are admixed as clusters and individual cells within the other 2 components is seen in multiple areas (Figs. 1A and D). Some of the ganglion cells are positive for synaptophysin, chromogranin, and neurofilament (Table 1). Third, the tumor has areas of a fasciculated proliferation of bland buckled spindle cells (Fig. 1C). These Schwann cells are S100 -positive and are admixed with numerous axons as demonstrated on the neurofilament stain (Fig. 1F). This bneuromatous Q component is found in large sheets as well as smaller bundles and is more haphazardly arranged than normal entrapped peripheral nerve. Immunohistochemical studies for different cytokeratins show striking results with positive staining not only in the paraganglioma component, but also in the ganglion cells and the axons of the ganglioneuromatous component (Fig. 1E and Table 1). Because of the presence of the intimately admixed areas of ganglioneuroma and paraganglioma, a diagnosis of a composite paraganglioma with areas of ganglioneuroma was made.
3. Discussion During embryonic development, neural crest cells of the sympathoadrenal (SA) lineage give rise to the adrenal medulla as well as the extraadrenal sympathetic paraganglia. Recent reviews summarize how the precursor cells of the SA lineage differentiate into sympathetic neurons, chromaffin neuroendocrine cells, and intermediate, small, intensely fluorescent cells. A number of factors guiding SA cell development have been identified, and cells at the different stages of development are characterized by specific expression profiles of different proteins [11,12]. SA lineage cells and their precursors are thought to give rise to a number of neoplasms related to different pathways and stages of SA cell differentiation, including neuroblastomas, ganglioneuroblastomas, ganglioneuromas, and paragangliomas/pheochromocytomas [12]. The occurrence of composite tumors with areas of divergent differentiation suggests that the pathways of differentiation open to cells of the SA lineage may not be mutually exclusive. In addition, a number of cell culture experiments have suggested that an acquired mature phenotype may not be a terminal stage of differentiation: Under appropriate conditions, chromaffin cells can be transformed into neuronal cells, and small, intensely fluorescent cells can bcross-differentiateQ into either chromaffin cells or neurons [12]. The case presented here shows morphologically and immunohistochemically distinct components with Schwannian, neuronal, and neuroendocrine differentiation. Cytokeratin expression, as mentioned, is frequently seen in paragangliomas of the cauda equina but is rare in paragangliomas of other sites [6,13]. In the reviewed studies of gangliocytic or ganglioneuromatous paragangliomas, the
P. Pytel et al. cytokeratin expression in the ganglion cells is either reported as negative [14], not reported separately [4] or not studied [2,3,5,9,10]. The fact that not only the neuroendocrine but also the ganglion cell component is positive for cytokeratins supports the conclusion that the neurons are part of the neoplasm and not entrapped bystander cells. In summary, this tumor illustrates the broad spectrum of divergent phenotypes that can be found in paragangliomas and serves to emphasize how our emerging knowledge of the SA cell lineage can help to understand the development of these diverse histological phenotypes.
References [1] Lack EE. Extra-adrenal paragangliomas of the sympathoadrenal neuroendocrine system. In: Lack EE, editor. Tumors of the Adrenal Gland and Extra-Adrenal Paraganglia. 3rd ed. Washington7 Armed Forces Institute of Pathology; 1995. p. 269 - 84. [2] Linnoila RI, Keiser HR, Steinberg SM, Lack EE. Histopathology of benign versus malignant sympathoadrenal paragangliomas: clinicopathological study of 120 cases including unusual histologic features. Hum Pathol 1990;21(11):1168 - 80. [3] Lerman RI, Kaplan ES, Daman L. Ganglioneuroma-paraganglioma of the intradural filum terminale. Case report. J Neurosurg 1972;36(5): 652 - 8. [4] Moran CA, Rush W, Mena H. Primary spinal paragangliomas: a clinicopathological and immunohistochemical study of 30 cases. Histopathology 1997;31(2):167 - 73. [5] Sonneland PR, Scheithauer BW, LeChago J, Crawford BG, Onofrio BM. Paraganglioma of the cauda equina region. Clinicopathologic study of 31 cases with special reference to immunocytology and ultrastructure. Cancer 1986;58(8):1720 - 35. [6] Chetty R, Pillay P, Jaichand V. Cytokeratin expression in adrenal phaeochromocytomas and extra - adrenal paragangliomas. J Clin Pathol 1998;51(6):477 - 8. [7] Tischler AS. Divergent differentiation in neuroendocrine tumors of the adrenal gland. Semin Diagn Pathol 2000;17(2):120 - 6. [8] Sakaguchi N, Sano K, Ito M, Baba T, Fukuzawa M, Hotchi M. A case of von Recklinghausen’s disease with bilateral pheochromocytoma– malignant peripheral nerve sheath tumors of the adrenal and gastrointestinal autonomic nerve tumors. Am J Surg Pathol 1996; 20(7):889 - 97. [9] Brady S, Lechan RM, Schwaitzberg SD, Dayal Y, Ziar J, Tischler AS. Composite pheochromocytoma/ganglioneuroma of the adrenal gland associated with multiple endocrine neoplasia 2A: case report with immunohistochemical analysis. Am J Surg Pathol 1997;21(1):102 - 8. [10] Schmitt HP, Wurster K, Bauer M, Parsch K. Mixed chemodectoma– ganglioneuroma of the conus medullaris region. Acta Neuropathol (Berl) 1982;57(4):275 - 81. [11] Langley K, Grant NJ. Molecular markers of sympathoadrenal cells. Cell Tissue Res 1999;298(2):185 - 206. [12] Hoehner JC, Hedborg F, Eriksson L, et al. Developmental gene expression of sympathetic nervous system tumors reflects their histogenesis. Lab Invest 1998;78(1):29 - 45. [13] Orrell JM, Hales SA. Paragangliomas of the cauda equina have a distinctive cytokeratin immunophenotype. Histopathology 1992; 21(5):479 - 81. [14] Hironaka M, Fukayama M, Takayashiki N, Saito K, Sohara Y, Funata N. Pulmonary gangliocytic paraganglioma: case report and comparative immunohistochemical study of related neuroendocrine neoplasms. Am J Surg Pathol 2001;25(5):688 - 93.
www.elsevier.com/locate/humpath
Ganglioneuromatous paraganglioma of the cauda equina—a pathological case study Peter Pytel MD, Thomas Krausz MD, FRCPath, Robert Wollmann MD, PhD, Manuel F. Utset MD, PhD* Department of Pathology, University of Chicago Hospitals, Chicago, IL 60637, USA Received 22 December 2004; revised 13 January 2005
Keywords: Divergent differentiation; Neural crest; Cytokeratin
Summary This study presents a rare case of compound paraganglioma/ganglioneuroma with comprehensive immunohistochemical studies that reveal strong cytokeratin expression in all components. A 74 - year - old woman presented with a mass lesion of the cauda equina. The 1.8 - cm tumor showed 3 histomorphologically and immunohistochemically distinct components: typical paragangliomatous neuroendocrine areas, mature ganglion cell-like neuronal areas, and a bneuromatousQ proliferation of Schwann cells with admixed axons. As often seen in cauda equina paragangliomas, the neuroendocrine cells were cytokeratin-positive. In addition, immunoreactivity for cytokeratins was also observed in the neurons and axons. This tumor illustrates the broad spectrum of divergent differentiation that can be seen in cells of sympathoadrenal lineage. D 2005 Elsevier Inc. All rights reserved.
1. Introduction Paragangliomas and pheochromocytomas are related neoplasms that are derived from neural crest cells. Paragangliomas occur in many different locations. In general, paragangliomas are regarded as low-grade tumors, but their prognosis varies depending on the site of origin. Histological features such as necrosis, high mitotic activity, coarse nodularity, and high proliferative index based on immunostaining with the monoclonal antibody (MAb) MIB1 may also correlate with biologic behavior [1,2]. The first report of a paraganglioma of the cauda equina was published in 1972 [3]. Since then, a number of case
T Corresponding author. E-mail address: [email protected] (M.F. Utset). 0046-8177/$ – see front matter D 2005 Elsevier Inc. All rights reserved. doi:10.1016/j.humpath.2005.01.024
reports and 2 larger studies of 31 cauda equina paragangliomas and of 30 spinal paragangliomas have been published [4,5]. These tumors show a slight male preponderance and a wide age distribution (13 -71 years, median approximately 50 years). Patients often present with lower back pain and leg pain, urinary and fecal incontinence, as well as sensory and motor deficits of the lower extremities. Imaging studies typically demonstrate a well-delineated mass lesion. In the cauda equina, the preoperative differential diagnosis includes ependymoma, meningioma, nerve -sheath tumors, and metastatic lesions. The pathology of cauda equina paragangliomas differs from those occurring in other locations in 2 features: (1) they more commonly show ganglion cell differentiation (up to 45%) [5] and (2) they often exhibit immunoreactivity for different cytokeratins [6]. The diagnosis of paragangliomas can be complicated by the fact that these tumors sometimes exhibit areas of
Ganglioneuromatous paraganglioma
445 tumor), these have been referred to as bcompositeQ or bcompoundQ tumors. In cases of a heterologous component (eg, adrenal cortical adenoma and spindle cell sarcoma), they have been referred to as bmixed tumors of the adrenal gland.Q There are a number of reported cases of homologous composite tumors occurring in patients with neurofibromatosis type 1 [8] and multiple endocrine neoplasia type 2A [9]. We are presenting a case of a composite tumor of the cauda equina with paraganglioma and ganglioneuroma components. Ganglion cell differentiation is, as mentioned, common in cauda equina paragangliomas [5], but a true ganglioneuromatous component is very unusual. To our knowledge, this tumor represents the fourth such reported case [3,10] occurring in the cauda equina, and this is the first report that includes immunohistochemical studies.
2. Case report
Fig. 1 Histomorphological findings. A, Mixed tumor with paraganglioma like neuroendocrine areas, peripheral nerve type Schwannian tissue, and ganglion cells. B, Paraganglioma component. C, Schwannian component with scattered ganglion cells. D, Mature ganglion cells. E, The cytokeratins demonstrate staining in the neuroendocrine cells as well as in ganglion cells and axons (Cam5.2 shown). F, Neurofilament staining highlighting the axons within the neuromatous component.
divergent differentiation [2,7]. There are a number of reports of paragangliomas and more commonly of pheochromocytomas containing divergent elements. In cases of a homologous component (eg, other neural crest derived elements such as neuroblastoma, ganglioneuroblastoma, ganglioneuroma, and malignant peripheral nerve sheath
The patient, a 74- year-old woman, presented with back and leg pain but did not have any weakness or other neurological deficits. The patient underwent surgical resection. Intraoperatively, an encapsulated tumor was observed that pushed the nerve roots of the cauda equina dorsally. The tumor was attached to a nerve root that ran within the tumor capsule. The resected specimen measured 1.8 cm and consisted of a firm nodular tumor with areas of hemorrhage. The specimen was fixed in 10% neutrally buffered formalin and embedded in paraffin. Sections were cut for hematoxylin/eosin staining as well as for immunohistochemical studies. These were performed with commercially available antibodies and according to standard protocols. Histologically, the tumor contains 3 main components (Fig. 1): It has vague cellular nodules of epithelioid cells with an organoid nested arrangement (Fig. 1B). These have the appearance of neuroendocrine cells and immunoreact with confirmatory markers (Table 1). Scattered S100positive sustentacular cells are identified within this
Table 1 Immunohistochemical staining of the neuroendocrine and neuronal components as well as of the axons and the Schwann cells of the ganglioneuromatous areas Cell type Neuroendocrine cells
Cam5.2 AE1
+++ Diffuse Ganglion cells ++/+++ Diffuse Neuromatous component: axons ++/+++ Diffuse Neuromatous component: Schwann cells
+ Focal +++ Focal ++ Focal
AE3
Syn
Chrom NF
+/++ Diffuse + Diffuse + Diffuse
++/+++ Diffuse +/++ Diffuse +/++ Diffuse
++ Focal + Focal
S100
+ Focal +/+++ Focal +++ Diffuse
GFAP MIB1 Rare positive cells (b3%)
++ Diffuse
Rare positive cells (b1%)
The staining intensity was graded as negative ( ) or as weakly, moderately, or strongly positive (+ to +++), and the distribution of the immunoreactivity was graded as bfocalQ or bdiffuse.Q Chrom indicates chromogranin; NF, neurofilament; Syn, synaptophysin. Antibody specificities: AE1, AE3, and Cam5.2; cytokeratins; Chrom, chromogranin; GFAP, glial fibrillary acidic protein; NF, neurofilament; S100, S100 protein; and Syn, synaptophysin.
446 neuroendocrine component. A component of mature ganglion cells that are admixed as clusters and individual cells within the other 2 components is seen in multiple areas (Figs. 1A and D). Some of the ganglion cells are positive for synaptophysin, chromogranin, and neurofilament (Table 1). Third, the tumor has areas of a fasciculated proliferation of bland buckled spindle cells (Fig. 1C). These Schwann cells are S100 -positive and are admixed with numerous axons as demonstrated on the neurofilament stain (Fig. 1F). This bneuromatous Q component is found in large sheets as well as smaller bundles and is more haphazardly arranged than normal entrapped peripheral nerve. Immunohistochemical studies for different cytokeratins show striking results with positive staining not only in the paraganglioma component, but also in the ganglion cells and the axons of the ganglioneuromatous component (Fig. 1E and Table 1). Because of the presence of the intimately admixed areas of ganglioneuroma and paraganglioma, a diagnosis of a composite paraganglioma with areas of ganglioneuroma was made.
3. Discussion During embryonic development, neural crest cells of the sympathoadrenal (SA) lineage give rise to the adrenal medulla as well as the extraadrenal sympathetic paraganglia. Recent reviews summarize how the precursor cells of the SA lineage differentiate into sympathetic neurons, chromaffin neuroendocrine cells, and intermediate, small, intensely fluorescent cells. A number of factors guiding SA cell development have been identified, and cells at the different stages of development are characterized by specific expression profiles of different proteins [11,12]. SA lineage cells and their precursors are thought to give rise to a number of neoplasms related to different pathways and stages of SA cell differentiation, including neuroblastomas, ganglioneuroblastomas, ganglioneuromas, and paragangliomas/pheochromocytomas [12]. The occurrence of composite tumors with areas of divergent differentiation suggests that the pathways of differentiation open to cells of the SA lineage may not be mutually exclusive. In addition, a number of cell culture experiments have suggested that an acquired mature phenotype may not be a terminal stage of differentiation: Under appropriate conditions, chromaffin cells can be transformed into neuronal cells, and small, intensely fluorescent cells can bcross-differentiateQ into either chromaffin cells or neurons [12]. The case presented here shows morphologically and immunohistochemically distinct components with Schwannian, neuronal, and neuroendocrine differentiation. Cytokeratin expression, as mentioned, is frequently seen in paragangliomas of the cauda equina but is rare in paragangliomas of other sites [6,13]. In the reviewed studies of gangliocytic or ganglioneuromatous paragangliomas, the
P. Pytel et al. cytokeratin expression in the ganglion cells is either reported as negative [14], not reported separately [4] or not studied [2,3,5,9,10]. The fact that not only the neuroendocrine but also the ganglion cell component is positive for cytokeratins supports the conclusion that the neurons are part of the neoplasm and not entrapped bystander cells. In summary, this tumor illustrates the broad spectrum of divergent phenotypes that can be found in paragangliomas and serves to emphasize how our emerging knowledge of the SA cell lineage can help to understand the development of these diverse histological phenotypes.
References [1] Lack EE. Extra-adrenal paragangliomas of the sympathoadrenal neuroendocrine system. In: Lack EE, editor. Tumors of the Adrenal Gland and Extra-Adrenal Paraganglia. 3rd ed. Washington7 Armed Forces Institute of Pathology; 1995. p. 269 - 84. [2] Linnoila RI, Keiser HR, Steinberg SM, Lack EE. Histopathology of benign versus malignant sympathoadrenal paragangliomas: clinicopathological study of 120 cases including unusual histologic features. Hum Pathol 1990;21(11):1168 - 80. [3] Lerman RI, Kaplan ES, Daman L. Ganglioneuroma-paraganglioma of the intradural filum terminale. Case report. J Neurosurg 1972;36(5): 652 - 8. [4] Moran CA, Rush W, Mena H. Primary spinal paragangliomas: a clinicopathological and immunohistochemical study of 30 cases. Histopathology 1997;31(2):167 - 73. [5] Sonneland PR, Scheithauer BW, LeChago J, Crawford BG, Onofrio BM. Paraganglioma of the cauda equina region. Clinicopathologic study of 31 cases with special reference to immunocytology and ultrastructure. Cancer 1986;58(8):1720 - 35. [6] Chetty R, Pillay P, Jaichand V. Cytokeratin expression in adrenal phaeochromocytomas and extra - adrenal paragangliomas. J Clin Pathol 1998;51(6):477 - 8. [7] Tischler AS. Divergent differentiation in neuroendocrine tumors of the adrenal gland. Semin Diagn Pathol 2000;17(2):120 - 6. [8] Sakaguchi N, Sano K, Ito M, Baba T, Fukuzawa M, Hotchi M. A case of von Recklinghausen’s disease with bilateral pheochromocytoma– malignant peripheral nerve sheath tumors of the adrenal and gastrointestinal autonomic nerve tumors. Am J Surg Pathol 1996; 20(7):889 - 97. [9] Brady S, Lechan RM, Schwaitzberg SD, Dayal Y, Ziar J, Tischler AS. Composite pheochromocytoma/ganglioneuroma of the adrenal gland associated with multiple endocrine neoplasia 2A: case report with immunohistochemical analysis. Am J Surg Pathol 1997;21(1):102 - 8. [10] Schmitt HP, Wurster K, Bauer M, Parsch K. Mixed chemodectoma– ganglioneuroma of the conus medullaris region. Acta Neuropathol (Berl) 1982;57(4):275 - 81. [11] Langley K, Grant NJ. Molecular markers of sympathoadrenal cells. Cell Tissue Res 1999;298(2):185 - 206. [12] Hoehner JC, Hedborg F, Eriksson L, et al. Developmental gene expression of sympathetic nervous system tumors reflects their histogenesis. Lab Invest 1998;78(1):29 - 45. [13] Orrell JM, Hales SA. Paragangliomas of the cauda equina have a distinctive cytokeratin immunophenotype. Histopathology 1992; 21(5):479 - 81. [14] Hironaka M, Fukayama M, Takayashiki N, Saito K, Sohara Y, Funata N. Pulmonary gangliocytic paraganglioma: case report and comparative immunohistochemical study of related neuroendocrine neoplasms. Am J Surg Pathol 2001;25(5):688 - 93.