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| PICTORIAL ESSAY: NEUROPATHOLOGY |
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| Year : 2014 | Volume
: 1
| Issue : 2 | Page : 124-131 |
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Diagnostic approach to histopathology of central nervous system papillary tumors
Ishita Pant, Sujata Chaturvedi
Department of Pathology, Institute of Human Behaviour and Allied Sciences, Delhi, India
| Date of Web Publication | 31-Jul-2014 |
Correspondence Address:
Dr. Ishita Pant
Department of Pathology, Institute of Human Behaviour and Allied Sciences, Dilshad Garden, Delhi - 110 095
India
 Source of Support: None, Conflict of Interest: None  | Check |
DOI: 10.4103/2349-0977.137855
Tumors of the central nervous system (CNS) exhibiting a papillary pattern constitute a remarkably diverse group of neoplasms that can occur at virtually any site and in patients of any age. Since the first classification of nervous system tumors in 1926, formulated by Percival Bailey and Harvey Cushing based on the presumed parallels between embryologic and neoplastic cells to the World Health Organization (WHO) classification of tumors of the CNS 2007, CNS tumors have come a long way. WHO classification of tumors of the CNS 2007, lists several new entities. However, despite the advancements and the rapid progress with various classification systems in place, as a first step, brain tumors are still characterized largely by the typical patterns and their histopathological features. This pictorial essay represents the histopathology of one of these patterns comprised of various papillary tumors of the CNS, highlighting the diagnostic approach. Keywords: Central nervous system tumors, histopathology, papillary
How to cite this article:
Pant I, Chaturvedi S. Diagnostic approach to histopathology of central nervous system papillary tumors. Astrocyte 2014;1:124-31 |
| Introduction | |  |
The fourth edition of the World Health Organization (WHO) classification of tumors of the central nervous system (CNS; 2007), currently lists more than 100 types of CNS tumors including their variants. Considering the diversity of these tumors, an organized approach is preferable to minimize the diagnostic errors. The first step of the diagnostic algorithm includes the clinical and radiologic features. Analysis of the clinical and radiologic features including the location (supratentorial versus infratentorial), age (adult versus pediatric), and radiology (enhancing versus nonenhancing tumors) narrows down the differential diagnosis to a great extent. The next step includes the analysis of histopathology, based on the histopathological patterns [Box 1.1], which provides a useful diagnostic algorithm. The combination of clinical, radiological, and histopathologic features forms the basis of diagnostic approach toward a CNS neoplasm.
CNS tumors showing papillary pattern
Papillary/pseudopapillary histopathological pattern is frequently observed in the brain biopsies received from the CNS tumors. CNS tumors exhibiting a papillary appearance, includes a diverse group of neoplasms that can occur at virtually any site and in patients of any age [Box 1.2]. This essay highlights the salient features of these tumors with special emphasis on the histopathology. Key features are summarized in [Table 1] and tumor-wise details given hereunder [Table 1]. | Table 1: Papillary CNS Tumors Diagnoses by Age, Location, and Histopathologic Features
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Choroid plexus tumors
Choroid plexus tumors are uncommon in adulthood, representing 2-4% of pediatric brain tumors and up to 20% of those arising within the first year of life. [1] This group comprises of three entities: Choroid plexus papilloma (CPP; WHO grade I), atypical CPP (WHO grade II), and choroid plexus carcinoma (CPC; WHO grade III). CPP and CPC are commonly encountered in the lateral ventricles (50%), fourth ventricle (40%), and third ventricle (5%), with two or more than two ventricles being involved in 5% cases. There is an overall male: female ratio of 1.2: 1; for lateral ventricles this ratio is 1:1 while for fourth ventricle tumors it is 3:2. Patients present with signs of hydrocephalus and raised intracranial pressure, either due to excess cerebrospinal fluid (CSF) production by the tumor itself or obstruction of CSF pathways.
Histopathology of CPP shows papillae having fibrovascular connective tissue fronds [Figure 1] lined by a single layer of uniform cuboidal to columnar epithelial cells with round to oval basally situated monomorphic nuclei [Figure 2]. Mitotic activity is exceptional. Atypical CPP shows similar histopathology with blurring of the papillary pattern at places and increased mitotic activity [Figure 3]. In contrast, CPC shows frank signs of malignancy. Immunohistochemically, CPP expresses cytokeratins (CK), vimentin, podoplanin, S-100 [Figure 4] and transthyretin while CPC express CK showing less frequent positivity for S-100 and transthyretin. Mean Ki-67/MIB-1 labeling indices reported for CPP and CPC are 1.9% and 13.8%, respectively. | Figure 1: Choroid plexus papilloma: Microphotograph shows fibrovascular papillae lined by monomorphic epithelial cells (H and E 100×).
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 | Figure 2: Choroid plexus papilloma: Microphotograph shows fibrovascular papillae lined by a single layer of monomorphic cuboidal to columnar epithelial cells (H and E 200×).
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 | Figure 3: Atypical choroid plexus papilloma: Microphotograph shows increased mitotic activity and architectural complexity (H and E 400×).
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 | Figure 4: Choroid plexus papilloma: Microphotograph shows strong cytoplasmic immunopositivity for S-100 in the fibrovascular papillae lined by monomorphic epithelial cells (S-100; 100×).
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Papillary ependymoma
Papillary ependymoma is generally a slow growing tumor affecting children and young adults, histologically corresponding to WHO grade II. It is most commonly seen in the fourth ventricle and spinal cord, followed by the lateral ventricles and the third ventricle. Supratentorial ependymomas manifest with focal neurological deficits, seizures, and features of intracranial hypertension; while infratentorial ependymomas present with hydrocephalus and raised intracranial hypertension.
Histopathologically, papillary ependymomas show papillae lined by single or multiple layer of cuboidal tumor cells [Figure 5] with smooth contiguous surfaces in addition to the perivascular pseudorosettes and the ependymal rosettes. It shows glial fibrillary acidic protein (GFAP) positivity in the pseudorosettes and the papillae [Figure 6]. Immunopositivity for S-100, vimentin, epithelial membrane antigen (EMA), and nestin is also seen.  | Figure 5: Papillary ependymoma: Microphotograph shows papillary structures lined by single and multiple layers of monomorphic cuboidal tumor cells (H and E 200×).
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 | Figure 6: Papillary ependymoma: Microphotograph shows GFAP immunoreactivity predominantly in the pseudorosettes (GFAP 400×).
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Myxopapillary ependymoma
Myxopapillary ependymoma is generally a slow growing tumor manifesting in young adults typically involving the conus medullaris, cauda equina, and filum terminale of the spinal cord and corresponds to WHO grade I. The frequency of this tumor is 9-13% among all ependymomas. [2] The mean age of 36 years has been reported with a male: female ratio of 2.2:1. It typically presents with back pain of long duration.
Histopathology of myxopapillary ependymoma shows cuboidal to elongated tumor cells arranged in papillae around vascularized myxoid stromal cores [Figure 7]. Mitotic activity is low. Immunohistochemistry for GFAP, S-100, and vimentin is positive. Prognosis is extremely favorable. | Figure 7: Myxopapillary ependymoma: Microphotograph shows tumor cells around vessels with mucoid degeneration (H and E 100×); myxoid matrix in inset (H and E 200×).
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Astroblastoma
Astroblastoma is a rare glial neoplasm mainly affecting children, adolescents, and young adults, typically involving the cerebral hemispheres. Due to the insufficient epidemiological and clinico-pathologic data, this tumor still awaits a WHO grade.
Histopathologically, it is a well circumscribed tumor showing perivascular arrangement of tumor cells imparting papillary as well as pseudopapillary appearances. Tumor cells are polygonal to spindle in shape showing round to oval irregularly indented nuclei with coarse chromatin. Blood vessels show hyalinization leading to fibrosis and focal areas of infarction. Cytoplasmic immunopositivity for vimentin, S-100, and GFAP is characteristic.
Papillary meningioma
Papillary meningiomas are rare tumors manifesting in younger patients, approximately 50% cases being reported in children. These are highly aggressive tumor corresponding to WHO grade III with a tendency to invade, recur, and metastasize. [3] Majority arise in intracranial (cerebral convexities), intraspinal (thoracic regions), or orbital locations. Among middle aged patients, the female: male ratio is 1.7:1. Clinically, headache and seizures are the common presenting features.
Histopathologically, these are cellular tumors characterized by a papillary or a pseudopapillary pattern resulting from discohesive meningothelial tumor cells and a perivascular arrangement of epithelioid tumor cells. Diagnosis of papillary meningioma is considered only when this architectural pattern is exhibited in > 50% of the tumor. Immunopositivity for EMA, vimentin, and S-100 is characteristic. Mean Ki-67/ MIB-1 labeling indices reported for papillary meningioma are generally > 20%.
Papillary glioneuronal tumor
Papillary glioneuronal tumor as a distinct entity was reported by Komori et al. in 1998 [4] and was included in WHO classification in 2000. This neoplasm being extremely rare still lacks a population-based epidemiologic data. This tumor manifest over a wide range of ages (4-75 years); the mean age at presentation being 27 years. [5],[6] There is no gender bias. It corresponds to WHO grade I. It shows a predilection for the temporal lobes. Headache and seizures are the main clinical features.
Histopathology shows a characteristic pseudopapillary architecture. Single or pseudostratified layer of small cuboidal glial cells with rounded nuclei and scant cytoplasm covers the hyalinized blood vessels. Diffuse as well as focal collection of neurocytes and occasional ganglion cells is seen in the interpapillary areas. Immunohistochemically, the glial cells are GFAP positive while the interpapillary cells are synaptophysin, neuron specific enolase (NSE), and NeuN positive. MIB-1 labeling indices are in the range of 1-2%.
Atypical teratoid/rhabdoid tumor
Atypical teratoid/rhabdoid tumor (ATRT) is a highly malignant CNS tumor (WHO grade IV), occurring most frequently in infants, with most patients being aged less than 3 years and rarely in children aged more than 6 years (mean age 2 years). [7] It is rarely seen in adults. Male: female ratio ranges from 1.6 to 2:1 showing a consistent male predominance. ATRTs account for 1-2% of pediatric brain tumors and approximately 10% of the infantile CNS tumors. [7] This tumor may occur in either supratentorial or infratentorial location, the ratio of supratentorial to infratentorial being 1.3:1. [8] Supratentorial tumors are common in the cerebral hemispheres while cerebellum is the most common infratentorial location. Clinical presentation depends upon the age at presentation, location, and the size of the tumor.
Histopathology of the ATRT shows a heterogeneous picture [Figure 8]. The most striking feature is the presence of rhabdoid cells showing eccentrically placed vesicular nuclei, prominent eosinophilic nucleoli, and abundant cytoplasm with eosinophilic cytoplasmic inclusions [Figure 9]. These cells may be arranged in nests, sheets, or may show jumbled appearance. However, these characteristic rhabdoid cells are usually intermingled with cells showing primitive neuroectodermal, mesenchymal, and epithelial features [Figure 10]. Papillary or gland-like features are rarely seen in ATRTs [Figure 11]. Immunohistochemical expression is also diverse. Rhabdoid cells are immunopositive for EMA, vimentin, and smooth muscle actin (SMA) [Figure 12]. Expression of GFAP, neurofilament protein (NFP), synaptophysin, and keratins are also common [Figure 13]. Currently, INI1 is considered the most sensitive and specific marker for ATRTs. Ki-67/MIB-1 labeling indices reported for ATRTs are often > 50%, focally up to 100% [Figure 14]. | Figure 8: ATRT: Microphotograph shows a cellular tumor with a variable appearance (H and E 100×).
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 | Figure 9: ATRT: Microphotograph shows large rhabdoid cells (H and E 200×); detailed morphology in inset (H and E 400×).
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 | Figure 10: ATRT: Microphotograph shows rhabdoid cells against a mesenchymal background (H and E 100×).
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 | Figure 11: ATRT: Microphotograph shows papillary pattern (H and E 200×).
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 | Figure 12: ATRT: Microphotograph shows strong immunopositivity for vimentin in the rhabdoid cells (vimentin 200×).
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 | Figure 13: ATRT: Microphotograph shows strong immunopositivity for synaptophysin (inset; synaptophysin 200×) and focal positivity for GFAP (GFAP 200×).
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 | Figure 14: ATRT: Microphotograph shows a high Ki 67 labeling index (Ki 67 200×).
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Papillary Craniopharyngioma
Papillary craniopharyngioma, the recently identified variant of craniopharyngioma, [9] typically affects the adults (mean age 40-55 years) involving the suprasellar region or the third ventricles. It is a benign tumor and corresponds histologically to WHO grade I. Craniopharyngiomas in general account for 1.2-4.6% of all intracranial tumors. Male and female are equally affected. Clinical features include visual loss, endocrine deficiencies, raised intracranial tension, diminished mental acuity, and personality changes.
In contrast to adamantinomatous craniopharyngioma, the papillary variant is solid and lacks both the motor oil content and calcification.
Histopathologically, papillary craniopharyngiomas are comprised of well differentiated nonkeratinizing squamous epithelium and a papillary fibrovascular stroma [Figure 15]. Intermingled pseudopapillae are the additional features resulting due to the dehiscence of the squamous epithelium. MIB-1 immunopositivity is randomly distributed and are considerably higher than might be expected considering the benign nature of the neoplasm. | Figure 15: Papillary craniopharyngioma: Microphotograph shows papillae formed by nonkeratinizing squamous epithelium (H and E 200×).
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Yolk Sac Tumor
WHO has classified the intracranial germ cell tumors into three categories: Germinomas, nongerminoamtous germ cell tumors, and teratomas. CNS yolk sac tumor belongs to the second category. The incidence of this tumor varies geographically. It has been reported in all age groups but majority affect patients aged younger than 25 years. This tumor is more common in males. Midline location (third ventricle, pineal region) is the most common followed by the suprasellar compartment. Clinical presentation varies according to the location.
Histopathology shows admixed morphologic patterns like reticular or microcystic, macrocystic, papillary, solid, and glandular pattern with the characteristic Schiller-Duval bodies. These bodies are formed by the tufts of malignant cuboidal to columnar cells surrounding the central blood vessels. Another diagnostically helpful finding is the presence of Periodic acid Schiff (PAS) positive/diastase resistant, variably sized, cytoplasmic hyaline globules lying within the epithelial cells or in the stroma. Mitosis is variable. Immunohistochemistry shows diagnostic cytoplasmic positivity for alpha fetoprotein (AFP).
Papillary tumor of the pineal region
Papillary tumor of the pineal region (PTPR) is a recently recognized rare neuroepithelial tumor that occurs exclusively in the pineal region, most often in adults. This entity was diagnosed in 2003 by Jouvet et al. [10] and formally codified in the WHO classification in 2007. Incidence is not determined till date because of the rarity of this neoplasm. Similarly histological grading criteria remain to be identified. PTPR has been identified in both children and in adults (mean age 32 years). There is no gender predilection. Most commonly it presents with features of obstructive hydrocephalus.
Histopathology of PTPR shows an epithelial tumor with papillary features and more dense cellular areas frequently forming true rosettes, perivascular pseudorosettes, and small tubules. The papillae are formed by the vessels covered by layers of large pale to eosinophilic columnar cells. Mitotic activity is variable ranging from 0 to 10/10 HPF. Foci of necrosis are present. Microvascular proliferation is usually not seen. Immunohistochemistry shows strong positivity for keratins in the papillary structures. PTPRs also show immunopositivity for vimentin, S-100, NSE, microtubule associated protein 2 (MAP2), Neural cell adhesion molecule (N-CAM), and transthyretin. [11],[12] The Ki-67/ MIB-1 labeling indices reported for PTPRs are moderate showing higher indices in tumors of young patients.
Metastatic Tumors of the CNS
Metastatic tumors are the most common CNS neoplasms. The incidence of CNS metastases increases from < 1/100,000 below 25 years of age to > 30/100,000 at the age of 60 years. [13] There is no gender predilection. The most common sources of brain metastases in adults are, in descending order, lung cancer, breast cancer, melanoma, renal cancer, and colon cancer; in children, in descending order, leukemia, lymphoma, osteogenic sarcoma, rhabdomyosarcoma, and Ewing sarcoma. The most common location for CNS metastases is the cerebral hemispheres, followed by cerebellum. Other sites include the dura and the leptomeninges.
Clinical manifestations are due to the raised intracranial pressure or due to the local effect of the tumor on the adjacent brain tissue. Symptoms may be gradually progressive and include headache, altered mental status, paresis, ataxia, visual complaints, nausea, or sensory disturbances.
Histopathology is diverse. Metastases of the carcinomas generally show a papillary pattern comprised of papillae formed by the fibrovascular cores lined by a single or multiple layers of pleomorphic tumor cells [Figure 16]. Tumor necrosis may be extensive. Mitotic activity is variable and marked [Figure 17]. Immunohistochemical expression is variable. CNS metastases of the carcinomas usually show strong immunopositivity for CK and EMA [Figure 18] and [Figure 19]. The Ki-67/MIB-1 labeling indices reported for metastatic tumors of the CNS are markedly high [Figure 20].  | Figure 16: Metastatic carcinoma: Microphotograph shows fibrovascular papillae lined by pleomorphic neoplastic epithelial cells (H and E 100×).
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 | Figure 17: Metastatic carcinoma: Microphotograph shows brisk mitotic activity (arrows) (H and E 200×).
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 | Figure 18: Metastatic carcinoma: Microphotograph shows strong immunopositivity for CK in the fibrovascular papillae lined by neoplastic epithelial cells (CK; 200×).
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 | Figure 19: Metastatic carcinoma: Microphotograph shows strong immunopositivity for EMA in the fibrovascular papillae lined by neoplastic epithelial cells (EMA; 200×).
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 | Figure 20: Metastatic carcinoma: Microphotograph shows a high Ki 67 labeling index (Ki 67 200×).
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The common thread unifying all the above-mentioned CNS tumors is the presence of a papillary pattern on histopathology. The clinical features, especially age and location, need to be taken into account while interpreting these. This pictorial essay aims to provide basic guidelines for the diagnosis of tumors of the CNS showing a papillary pattern on histopathology.
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[Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6], [Figure 7], [Figure 8], [Figure 9], [Figure 10], [Figure 11], [Figure 12], [Figure 13], [Figure 14], [Figure 15], [Figure 16], [Figure 17], [Figure 18], [Figure 19], [Figure 20]
[Table 1]
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