(20-21) Autopsy of a posterior third ventricular mass that invades midbrain tegmentum shows cysts , hemorrhage . Microscopy showed ependymal differentiation. Tumor would now likely be classified as PTPR. (Courtesy R. Hewlett, MD.)

differentiation, the major imaging differential diagnosis, have been described.

PAPILLARY TUMOR OF THE PINEAL REGION

Etiology and Pathology

•Probably arises from subcommissural organ

○In posteroinferior wall of third ventricle

○Ependymal differentiation

○Chromosome 10 loss

○Transcription factor SPDEF overexpressed

•WHO grade II or III

○Histologic grading criteria not yet defined

Clinical Features

•Adults

○Mean age at diagnosis = 32 years

•Local recurrence common; CSF dissemination rare

○Two subgroups defined by methylation profiling

○Hypermethylated tumors have shorter progression-free survival

Imaging

•Nonspecific

•Large, lobulated, heterogeneously enhancing mass

Differential Diagnosis

•Pineal parenchymal tumor of intermediate differentiation

•Germinoma

(20-22) Sagittal T1 C+ scan of a PTPR shows an enhancing pineal mass causing obstructive hydrocephalus. These imaging findings are nonspecific. (Courtesy P. Burger, MD.)

Germ Cell Tumors

Overview of Germ Cell Tumors

Intracranial germ cell tumors (GCTs) are rare neoplasms that vary in histologic differentiation, prognosis, and clinical behavior.

GCTs are divided into two basic groups, germinomas and nongerminomatous germ cell tumors. Germinomas comprise the larger group and represent approximately two-thirds of all GCTs. The smaller group consists of nongerminomatous GCTs (NGGCTs), which includes both teratomas and a heterogeneous group of "other" nongerminomatous malignant germ cell neoplasms.

We begin with an overview of intracranial GCTs, then discuss germinomas, teratomas, and the "other" germ cell tumors in greater detail.

Terminology

Intracranial GCTs are morphologic and immunophenotypic homologs of similar neoplasms that arise in the gonads and extragonadal sites. They are given the same names as their extracranial counterparts, i.e., germinoma, embryonal carcinoma, yolk sac tumor, choriocarcinoma, teratoma, and mixed GCT.

Etiology

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germ layers (ectoderm, mesoderm, and endoderm). Recent genome-wide studies show that primary intracranial GCTs have a methylation profile strongly resembling that of primordial germ cells at the migration phase.

Pure germ cell tumors and NGGCTs as well as CNS and testicular GCTs show similar mutational profiles, suggesting that all GCTs share a common molecular pathogenesis. The dominant genetic drivers of GCTs regardless of site of origin are activation of the mitogen-activated protein kinase (MAPK) and/or phosphoinositide 3-kinase (PI3K) pathways, indicating that they develop from a common ancestral cell.

Pathology

Although GCTs can arise in many intracranial locations, they have a distinct affinity for the midline (i.e., the pineal region, around the third ventricle, and the pituitary infundibulum) or very near the midline (i.e., basal ganglia).

(20-23A) Autopsy specimen shows a pineal germinoma .(Courtesy R. Hewlett, MD.) (20-23B) Submentovertex view of the basal cisterns in the same case shows diffuse CSF tumor ("carcinomatous meningitis") filling the suprasellar cistern and coating the brain. (Courtesy R. Hewlett, MD.)

(20-24) Sagittal graphic depicts typical pineal germinoma . CSF dissemination to the third, lateral, and fourth ventricles is common, as is subarachnoid tumor spread . (20-25) Classic germinoma consists of large round cells with prominent nucleoli, admixed with small lymphocytes. (Courtesy T. Tihan, MD.)

GCTs are classified according to histologic features and immunohistochemical profiles. They vary in malignancy from mature teratomas to poorly differentiated, highly aggressive neoplasms such as embryonal carcinoma, choriocarcinoma, and endodermal sinus (yolk sac) tumors. Histologically mixed lesions are common.

Clinical Issues

GCTs account for 0.5-3.5% of all brain tumors but 3-8% of primary CNS neoplasms in children. Prevalence is location dependent. In Asia, GCTs cause 8-15% of pediatric brain tumors.

GCTs are generally tumors of children and young adults; 8090% of patients are younger than 20 years of age. Many GCTs secrete oncoproteins such as α-fetoprotein or β-hCG, so laboratory evaluation and imaging are both key to diagnosis. Prognosis and treatment vary with tumor type.

INTRACRANIAL GERM CELL TUMORS

Pathology

•Homologs of gonadal neoplasms

○Germinoma, teratoma, choriocarcinoma, etc.

•Neoplastic correlates of primitive ectoderm, mesoderm, endoderm

•Propensity to arise in/near midline

Clinical Issues

•3-8% of primary CNS tumors in children

○More common in Asia (9-15% of pediatric brain tumors)

•Generally affect children, young adults

○80-90% < 20 years old

•Many secrete oncoproteins (α-fetoprotein, β-hCG)

•Treatment, prognosis vary with tumor type

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Germinoma

Terminology

Although germinomas are also called dysgerminoma or extragonadal seminoma, "germinoma" is the preferred term. The old name, "atypical teratoma," is confusing and no longer used.

Pathology

Location. Intracranial germinomas have a distinct predilection for midline structures (20-23). Between 80-90% "hug" the midline, extending along the midline axis from the pineal gland to the suprasellar region. One-half to two-thirds are found in the pineal region with the suprasellar region the second most frequent location, accounting for one-quarter to one-third of germinomas.

(20-26A) Postventriculostomy NECT scan in a 19y man shows hyperdense pineal mass

"engulfing" pineal gland calcifications . (20-26B) Sagittal T1WI in the same patient shows a well-defined pineal mass

compressing the tectal plate inferiorly , causing severe obstructive hydrocephalus.

(20-26C) T2WI in the same patient shows mixed signal intensity in the mass . Note severe obstructive hydrocephalus with "halo" of fluid around both temporal horns . (20-26D) T2* shows "blooming" hypointensities around and within the mass, probably a combination of hemorrhage and calcification.

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Nongerminomatous subtypes predominate at other sites. Offmidline germinomas occur in only 5-10% of cases. The basal ganglia and thalami are the most common off-midline sites.

Size and Number. Size at diagnosis varies with location. Some infundibular stalk germinomas become symptomatic (usually causing central diabetes insipidus) before they can be detected on high-resolution contrast-enhanced MRs. Pineal germinomas that do not invade the tectum or cause hydrocephalus can be as large as several centimeters at the time of initial diagnosis.

Approximately 20% of intracranial germinomas are multiple. The most frequent combination is a pineal plus a suprasellar ("bifocal" or "double midline") germinoma (20-24). Whether these are metastatic or synchronous lesions is debated.

Gross Pathology. Germinomas are generally solid, friable, tanwhite masses that often infiltrate adjacent structures.

(20-26E) Sagittal T1 C+ FS scan in the same patient shows that the mass enhances intensely. Note tumor in the anterior recesses of the third ventricle and along the floor of the fourth ventricle . (20-26F) Axial T1 C+ FS shows the enhancing mass and sulcal-cisternal enhancement suggesting CSF dissemination.

(20-26G) DWI shows diffusion restriction . (20-26H) ADC map shows moderate restriction consistent with a highly cellular mass. This was confirmed as germinoma.

Intratumoral cysts, small hemorrhagic foci, and CSF dissemination are common (20-23).

Microscopic Features. Germinomas are histologically similar to ovarian dysgerminoma and testicular seminoma. A pure germinoma consists of large, relatively undifferentiated cells with prominent nucleoli arranged in monomorphous sheets or lobules separated by fine fibrovascular septa.

Nearly all germinomas have a biphasic pattern of abundant reactive lymphocytes—usually dominated by T cells—intermixed with large round germinoma cells with prominent nucleoli (20-25). Some tumors exhibit such a florid lymphoplasmacellular reaction that it can obscure the neoplastic elements. Occasionally germinomas provoke an intense granulomatous response that mimics sarcoidosis or tuberculosis.

Mitotic activity is common and may even be conspicuous, but frank necrosis is rare.

Clinical Issues

Epidemiology. Germinoma is the most common intracranial GCT and accounts for 1-2% of all primary brain tumors.

Demographics. More than 90% of patients are younger than 20 years of age at initial diagnosis. Peak presentation is 10-14 years. The M:F ratio for pineal germinoma is 10:1. Suprasellar germinomas have no sex predilection.

Presentation. Presentation varies with location. Pineal germinomas typically present with headache and Parinaud syndrome. The most common presentation for suprasellar germinoma is central diabetes insipidus. Visual loss and precocious puberty are other presentations.

CSF cytology is rarely positive for tumor cells. Elevated serum or CSF markers (α-fetoprotein, β-HCG) are rare in pure germinomas but common with mixed GCTs.

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Natural History. CSF dissemination and invasion are common, but pure germinomas have a very favorable response to radiation therapy. The five-year survival for treated patients with pure germinoma is greater than 90%.

Germinomas that contain syncytiotrophoblastic giant cells have a higher recurrence rate and reduced long-term survival.

Treatment Options. Histologic documentation followed by radiation therapy is the standard first-line treatment. Adjuvant chemotherapy is reserved for disseminated tumors although the KIT/RAS and AKT1/mTOR pathways are potential therapeutic targets.

"Relapsed" patients are often salvaged with either standarddose chemotherapy and reirradiation or high-dose chemotherapy plus autologous stem cell rescue, with or without reirradiation. Patients with relapsed germinoma have better overall survival than relapsed NGGCTs.

(20-27A) Axial T2WI in a

24y man with severe headaches shows two bizarre-appearing masses: one in the pineal gland has multiple cysts . The other tumor—in the basal ganglia and corpus callosum—has multiple cysts, some of which contain hemorrhage .

(20-27B) The basal ganglionic-corpus callosum mass contains multiple small cysts and a large cyst in the left frontal lobe . The pineal mass extends anteriorly into the medial thalami.

(20-27C) T1 C+ FS in the same case shows that the pineal/thalamic mass enhances intensely . The cyst walls of the basal ganglionic-callosal-frontal lobe mass also enhance. (20-27D) More cephalad T1 C+ shows enhancing tumor along the ependymal surfaces of the left frontal horn and third ventricle/thalami . This is a germinoma.

GERMINOMA: PATHOLOGY AND CLINICAL ISSUES

Pathology

•Involve midline structures (80-90%)

•Pineal > > suprasellar > basal ganglia

•Can be multiple (20%)

○Most common = pineal + suprasellar

•Biphasic microscopic pattern

○Prominent population of reactive lymphocytes

○Large primordial germ cells with prominent nucleoli

•"Inflammatory" germinoma

○Intense granulomatous response

○Can cause confusion with TB, sarcoid

Clinical Issues

•1-2% of all neoplasms (more common in Asia)

•Most common intracranial GCT

•> 90% of patients < 20y

•Pineal germinoma, M:F = 3-10:1; suprasellar, M = F

•May cause diabetes insipidus before infundibular lesion seen at imaging!

Imaging

General Features. CSF dissemination is common, so the entire neuraxis should be imaged in patients with suspected germinoma. MR is the procedure of choice for complete delineation of germinoma extent. Caution: some suprasellar germinomas may present with diabetes insipidus long before lesions are visible on MR. In such cases, serial imaging should be performed.

CT Findings. Because nearly all germinomas contain numerous lymphocytes, they are typically hyperdense compared with brain on NECT. They appear to be "draped" around the posterior third ventricle. Obstructive hydrocephalus is variable. Pineal calcifications are "engulfed" and surrounded by tumor (20-26A).

Strong uniform enhancement on CECT is typical. Nearly 20% of germinomas are multiple, so look carefully for a second lesion in the suprasellar region (anterior 3rd ventricle recesses, infundibular stalk) (20-26E)!

MR Findings. Germinomas are isoto slightly hyperintense to cortex on T1and T2WI (20-26). Variably sized intratumoral cysts are common, especially in larger and "ectopic" lesions. Hemorrhage is generally uncommon except in basal ganglionic germinomas (20-27). T2* (GRE, SWI) may show "blooming" due to intratumoral calcification. Enhancement is strong and usually homogeneous. Because of their high cellularity, germinomas may show restricted diffusion (20-26).

"Inflammatory" germinomas may show extensive, nonenhancing peritumoral T2/FLAIR hyperintensity that extends into adjacent structures, such as the midbrain and thalami (20-28). In such cases, biopsies—especially small stereotaxic samples—may disclose only granulomatous reaction and be mistaken for TB or neurosarcoid.

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Differential Diagnosis

The major differential diagnosis of pineal germinoma is mixed germ cell tumor as well as nongerminomatous germ cell tumors. NGGCTs tend to be larger than germinomas at diagnosis, contain T1 hyperintense foci, enhance more strongly, and have higher mean ADC values. Bifocal lesions are almost always germinomas.

Some pineoblastomas may appear similar to germinoma but "explode" rather than "engulf" pineal calcifications. Pineal parenchymal tumor of intermediate differentiation usually occurs in middle-aged and older adults.

The major differential diagnosis of suprasellar germinoma is

Langerhans cell histiocytosis (LCH). Both are common in children, often cause diabetes insipidus, and may be indistinguishable on imaging studies alone. However, LCH does not produce oncoproteins. Neurosarcoidosis in an adult can cause a suprasellar mass that resembles germinoma.

GERMINOMA: IMAGING AND DDx

CT

•NECT: Hyperdense, "engulfs" pineal Ca++

•CECT: Enhances strongly, uniformly

MR

•T1 iso-/hypointense, T2 iso-/hyperintense

•Inflammatory germinomas may have extensive peritumoral T2/FLAIR hyperintensity

•GRE shows Ca++, hemorrhage

•Often restricts on DWI

•Enhances intensely, heterogeneously

•CSF spread common (look for other lesions)

○Anteroinferior 3rd ventricle, infundibular stalk

•Image entire neuraxis before surgery!

Differential Diagnosis

•Nongerminomatous GCT

•PPTs (pineoblastoma, PPTID)

•Histiocytosis (stalk lesion in child)

•Neurosarcoidosis (stalk lesion in adult)

Teratoma

Teratomas are tridermic masses that originate from "misenfolded" or displaced embryonic stem cells. Teratomas recapitulate somatic development and differentiate along ectodermal, mesodermal, and endodermal cell types.

Although they may originate anywhere in the body, teratomas are most commonly found in sacrococcygeal, gonadal, mediastinal, retroperitoneal, cervicofacial, and intracranial locations. Teratomas preferentially involve the midline; intracranial lesions most often arise in the pineal or suprasellar region.

Teratomas account for 2-4% of primary brain tumors in children and almost half of all congenital (perinatal) brain tumors. They account for more than 60% of prenatally detected parenchymal brain tumors.

(20-29) Graphic showcases a pineal teratoma with the typical heterogeneous tissue components (cysts, solid tumor, calcifications, fat, etc.).

Teratomas are more common in Asians and male patients. They have two peaks in age distribution. Ten percent occur before 5 years of age; nearly half occur from 5-15 years of age. Age at diagnosis is an important prognostic feature, independent of tumor location. Perior antenatal presentation is associated with higher risk of adverse outcome. Clinical behavior also varies significantly with tumor size.

There are three recognized types of teratoma. These range from a benign well-differentiated "mature" teratoma to an immature teratoma to a teratoma with malignant differentiation. All three share some imaging features, such as complex masses with striking heterogeneity in density and/or signal intensity. Cysts and hemorrhage are common.

Mature Teratoma

Mature teratomas are well-demarcated lobulated tumors that are composed entirely of fully differentiated adult-type elements from two or three embryonic germ layers. Ectodermal elements such as skin, hair, and dermal appendages (e.g., sebaceous glands) as well as CNS tissue are common (20-29). Mesodermal elements such as cartilage, bony spicules, teeth, adipose tissue, and muscle may be prominent features. Mucinous-appearing intratumoral cysts are common and are often lined with respiratory or gastrointestinal epithelium (20-30).

Mitotic activity is low or absent. A mature teratoma is a WHO grade I lesion.

The size of a mature teratoma varies from relatively small pineal lesions to huge holocranial lesions with massive extracranial extension into the orbit, face, ears, and oral cavity.

(20-30) Gross pathology of pineal teratoma shows a well delineated heterogeneous mass with a lobulated surface containing cysts , fat , and connective tissue . (From Ellison, Neuropathology, 3e.)

The intracranial component of these craniofacial teratomas may become so large that there is virtually complete loss of normal intracranial architecture. In such cases, normal brain structures are basically unrecognizable.

Imaging shows a complex-appearing multiloculated lesion with fat, calcification, numerous cysts, and other tissues (2031). Hemorrhage is common. Enhancement is variable.

Immature Teratoma

Immature teratomas contain a complex admixture of at least some fetal-type tissues from all three germ cell layers in combination with more mature tissue elements (20-32) (2033). It is common to have cartilage, bone, intestinal mucous, and smooth muscle intermixed with primitive neural ectodermal tissue. Hemorrhage and necrosis are common.

Giant immature teratomas are congenital lesions usually seen in a fetus or newborn. Most are associated with stillbirth, perinatal death, or significant morbidity after attempted surgical resection.

The fetal ultrasound diagnosis of intracranial teratoma can generally be established relatively early in pregnancy (15-16 weeks). Macrocephaly, progressive hydrocephalus, and polyhydramnios are common. A rapidly growing heterogeneous mass with mixed hyperand hypoechogenic features is typical.

CT or MR demonstrate almost complete replacement of brain tissue by a complex mixed-density or signal intensity mass

(20-34) (20-35).

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(20-32) Fetal autopsy case shows a large intraand extracranial immature teratoma with multiple cysts and hemorrhage.

(20-33) Autopsy of congenital teratoma shows a heterogeneous mass occupying most of the brain . (Courtesy T. Tihan, MD.)

Teratoma With Malignant Transformation

Teratomas with malignant transformation generally arise from immature teratomas and contain somatic-type cancers such as rhabdomyosarcoma or undifferentiated sarcoma.

INTRACRANIAL TERATOMAS

Pathology

•Arise from totipotential germ cells

•Tridermic with cells derived from all 3 germ cell layers

•3 types

○Mature teratoma (most common; well differentiated)

○Immature teratoma (some incompletely differentiated tissue)

○Teratoma with malignant transformation

Clinical Issues

•Only 3-4% of all teratomas are in CNS

•40-50% of all congenital brain tumors

Imaging

•Large holocranial/extracranial lesion in newborn?

○Most likely teratoma

○Distorts skull/brain, splits sutures

○Intracranial structures may be unrecognizable

○May extend through skull base into oral cavity

○Mixed density/signal intensity

○Cysts, hemorrhage common

•Pineal teratoma

○Mixed density, signal intensity

○Fat, Ca++, bone, cysts common

○Often causes obstructive hydrocephalus

Other Germ Cell Neoplasms

Germinomas are by far the most common of the germ cell neoplasms. Nongerminomatous malignant germ cell tumors (NGMGCTs) are rare neoplasms that contain undifferentiated epithelial cells and are often mixed with other germ cell elements (most often germinoma). These include yolk sac (endodermal sinus) tumor, embryonal carcinoma, choriocarcinoma, and mixed germ cell tumor.

NGMGCTs generally occur in adolescents with a peak incidence at 10-15 years of age. Prognosis is usually poor with overall survival less than 2 years.

Differentiating intracranial germ cell neoplasms on the basis of imaging studies alone is problematic. All intracranial GCTs—whether benign or malignant—tend to "hug" the midline. Many express different oncoproteins, so immunohistochemical profiling is an essential part of diagnosis.

Yolk Sac Tumor

Yolk sac (endodermal sinus) tumors represent just 2% of all intracranial GCTs. Yolk sac tumors are composed of primitive epithelial cells in a loose, variably cellular myxoid matrix. Peak occurrence is in the second decade. Imaging features are nonspecific.

Embryonal Carcinoma

(20-34) Postmortem T1WI of a newborn shows a complex holocranial mass of mixed signal intensity. This is immature teratoma.

Embryonal carcinoma is another tumor that contains large, anaplastic epithelioid cells that are arranged in sheets, cords, and nests.

Imaging findings are nonspecific and may be indistinguishable from germinoma (20-36).

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(20-36A) Sagittal T1WI in a 22y man with headaches, diabetes insipidus shows a sellar/suprasellar mass , pineal lesion .

(20-36B) Coronal T2WI shows that the intra/suprasellar mass appears moderately hypointense.

(20-36C) Both masses enhance strongly but heterogeneously on T1 C+ FS. This is embryonal carcinoma.

Choriocarcinoma

Most choriocarcinomas develop within or outside the uterus following a gestational event ("gestational" choriocarcinoma). Nongestational choriocarcinomas can arise from germ cells in gonadal or extragonadal midline locations.

CNS choriocarcinoma can be primary or metastatic, arising from an extracranial site such as the retroperitoneum or mediastinum. Primary intracranial choriocarcinoma (PICCC) is the rarest, most malignant of all the intracranial GCTs.

PICCCs are dimorphic tumors characterized by extraembryonic differentiation along cytotrophoblastic and syncytiotrophoblastic lines. They are composed of mononucleated trophoblastic cells admixed with large multinucleated syncytiotrophoblastic cells. Hemorrhage, necrosis, fibrosis, and neovascularity are common.

PICCCs typically present in patients 3-20 years of age. There is a nearly 4:1 male predominance. Precocious puberty is the most common presentation in male patients. Markedly elevated serum hCG/β-hCG levels are strongly suggestive of PICCC.

The most common sites of PICCC are the pineal and suprasellar regions. MR is helpful for tumor localization, characterization, and preoperative evaluation, but the findings are nonspecific. Intratumoral hemorrhages with stripe-like or patchy hypointensities on T2WI are common. Heterogeneous rim and nodular enhancement is seen in most cases. Extraneural/CSF metastases are common.

Mixed Germ Cell Tumor

Mixed GCTs are composed of any of the above histologic subtypes, often together with germinomatous elements. Mixed GCTs are more common than any pure germ cell lesion except for germinoma. Imaging findings are nonspecific (20-37).

"Other Cell" Pineal and Pineal

Region Neoplasms

Miscellaneous Pineal Neoplasms

Rarely, tumors arising within the pineal gland are composed of neoplastic elements other than parenchymal or germ cells. Primary glial neoplasms such as astrocytoma (including glioblastoma) (20-38) and oligodendroglioma (20-39) can occur within the pineal gland itself as can melanoma arising from pineal melanocytes (20-40). Metastases from extracranial sources also occasionally present as pineal masses (20-41).

In general, imaging findings with intrinsic pineal gland masses are nonspecific and do not permit differentiation between the broad spectrum of histologic types, so biopsy is necessary to guide patient management.

Miscellaneous Pineal Region Masses

Neoplasms and nonneoplastic masses in the pineal region can also originate from nongland structures such as the tectal plate, third ventricle, meninges of the tentorial apex, and the CSF spaces (20-42) (20-43). A general approach to evaluating pineal region masses is delineated in the box below.

APPROACH TO PINEAL REGION MASSES

Key Questions to Consider

•Is the mass in the pineal gland itself?

○If not, can you determine its anatomic origin?

•What is the patient's age, sex?

•Is there serum or CSF evidence of oncoproteins?

•Is there imaging evidence for other lesions?

○Pineal + suprasellar usually = germinoma

○Pineal + CSF spread usually = GCT, metastasis

Pineal Gland Mass

•Common

○Pineal cyst (nonneoplastic)

•Less common

○Pineocytoma

○Germinoma

•Rare but important

○Pineal parenchymal tumor of intermediate differentiation

○Pineoblastoma

○"Trilateral retinoblastoma"

○Teratoma (mature or immature)

○Nongerminomatous malignant germ cell tumor

○Papillary tumor of the pineal region

○Glioma (astrocytoma, oligodendroglioma)

○Metastasis

○Melanoma

Pineal Region Mass

•Common

○Intrinsic masses of the pineal gland itself (see above)

•Less common (masses outside pineal gland)

○Arachnoid cyst

○Dermoid cyst

○Epidermoid cyst

○Astrocytoma (tectal glioma)

○Meningioma (tentorial apex)

○Lipoma

○Metastasis

•Rare but important

○Vascular malformation (vein of Galen malformation, dural arteriovenous fistula)

○Vertebrobasilar dolichoectasia

○Basilar tip aneurysm

○Schwannoma (CNs III, IV)

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(20-37A) NECT in a 19y man with diabetes insipidus shows a partially calcified hyperdense suprasellar mass .

(20-37B) Sagittal T1WI shows mass infiltrates pituitary gland , infundibulum/third ventricle, contains scattered foci of T1 shortening .