Competing interest statement
Conflict of interest: the authors declare no potential conflict of interest.
Pineal region tumors represent less than 1% and 3-8% of brain tumors in adults and children respectively. There is a wide range of pineal masses, with the majority being germ cell and pineal parenchymal tumors. Magnetic resonance imaging (MRI) is the modality of choice for the assessment of pineal masses. It is considered as the gold standard for the evaluation of the central nervous system. MRI has the ability to produce very detailed images of the brain anatomy and is used to distinguish true pineal masses from parapineal with invasion of the gland. Specific MRI findings are helpful to the differential diagnosis of pineal tumors and the distinction between benign from malignant tumors. Pineal neoplasms may seed the subarachnoid space resulting in the development of intradural extramedullary metastases, known as drop metastases. MRI is the most sensitive method for the assessment of the spinal cord, meninges and nerve roots and the differentiation of the spinal lesions into intra/extra medullary and extradural. Because of its high sensitivity and the advances of the method, drop metastases can be easily diagnosed at an earlier stage than in the past, contributing to the selection of the appropriate treatment. Therefore, the entire neuroaxis should be investigated with MRI for the presence of intradural extramedullary lesions. The present study focuses on the main MR imaging characteristics of pineal masses and drop metastases with reference to the differential diagnosis. There is also a detailed approach to the MR protocol which should be obtained in order to evaluate the lesions.
Pineal region tumors are rare compared to other brain neoplasms. They constitute less than 1% and 3-8% of brain tumors in adults and children respectively.1-3 Magnetic resonance imaging (MRI) is the modality of choice for the assessment of pineal masses. It is considered to be the gold standard for the evaluation of the central nervous system (CNS). MRI has the ability to visualize anatomical details of the brain and separate true pineal masses from parapineal with invasion of the gland. Specific MRI findings are helpful in the differential diagnosis of pineal tumors and the distinction between benign from malignant tumors. Pineal region tumors can spread through the subarachnoid space into the spinal canal resulting in the development of intradural extramedullary metastases, also known as drop metastases. MRI is the diagnostic method of choice for the detection of spinal metastases and plays a critical role in the therapeutic approach of these patients.
The present study focuses on the main MR imaging features of pineal masses and drop metastases with reference to the differential diagnosis. There is also detailed approach to the MR protocol which should be obtained in order to evaluate the lesions. Computed tomography (CT) also plays an important role and often constitutes the first imaging method but its value is decreased specifically due to the radiation and the reduced resolution compared to MRI.
Normal anatomy of pineal region
The pineal gland is a small (5-8 mm AP diameter), pine-cone shaped, midline brain structure. It is located in the quadrigeminal cistern posteriorly to the third ventricle, inferiorly to the splenium of the corpus callosum and the internal cerebral veins and superiorly to the tectal plate of midbrain. The presence of calcifications with a diameter greater than 1 cm or before the age of 10 is mainly pathologic. The choroidal branches of the posterior cerebral artery are the feeding vessels of the gland.
Pineal gland tumors
There is a wide range of pineal region masses due to the multiple different cell types found there. Tumors arising from the pineal gland are mainly classified into germ cells and pineal parenchymal tumors.
Germ cell tumors are the most common, representing more than 50% of pineal tumors.4 They are divided into non-germinomatous and germinomatous. Based on the literature, germ cell tumors affecting the pineal region most frequently occur in males, especially non-germinomatous tumors with an incidence of 90%.5,6
Germinomas constitute the majority, accounting for 60-80% of all germ cell intracranial neoplasms, 3-5% of intracranial tumors in children and 0.4-1% of intracranial tumors in adults.5
Non-germinomatous germ cell tumors (teratomas, embryonal carcinomas, choriocarcinomas and yolk sac carcinomas) are rare. Teratomas are the second more common germ cell tumor in the pineal gland.3
Tumors arising from pineal parenchyma account for 14-27% of pineal gland tumors.7 Pineocytoma, pineoblastoma, pineal parenchymal tumor of intermediate differentiation (PPTID) and papillary tumor of the pineal region (PTPR) are included. Pineocytomas are reported to account for up to 30% of pineal tumors. Pineoblastoma is a common malignant tumor detected to the pineal region, with an incidence up to 50%. PPTID are less often, but account for at least 20% of this category of tumor.8
The remaining 25% of pineal region lesions include pineal cysts masses expanding from adjacent anatomical structures, such as gliomas arising from the adjacent brain parenchyma and meningiomas arising from the tentorium. Lipomas, pineal cysts, metastases and arachnoid cysts are also included.
Germinomas are mainly seen in children and young adults, with a peak at the age of 10-12. Approximately, 90% of the patients are less than 20 years old at the time of diagnosis.9 Germinoma is histologically similar to dysgerminoma of the ovary and seminoma of the testis.10 It is identified in the pineal region (50-65%), the suprasellar region (30%) and the basal ganglia-thalamus (5-10%).11 Germinomas are mainly aggressive tumors that often infiltrate the adjacent anatomical structures and spread through the cerebrospinal fluid (CSF) into the spinal canal.
Teratomas are distinguished in mature, immature and those with malignant transformation, with Alpha fetoprotein (AFP) and Human chorionic gonadotropin (HCG) elevated in immature type. Teratomas more often occur in children under 10 years of age. The most common location is the pineal region, but they may also occur in the third ventricle and posterior fossa. The rest of the non-germinomatous germ cell tumors are highly malignant. AFP and HCG in CSF are elevated in yolk sac carcinoma and choriocarcinoma respectively.7
Pineocytomas (WHO 2016, grade I) are benign tumors, most commonly presented in adults with a mean age of 38 years old.7 It is extremely rare for them to metastasize and spread into the spinal canal.9,12
Pineoblastomas (WHO 2016, grade IV) are highly malignant tumors mainly affecting children and young adults under 20 years old. The tumor infiltrates adjacent anatomical structures and often spreads into the spinal canal.
PPTID (WHO 2016, grade II or III) has histological features between those of pineocytoma and pineoblastoma without an age restriction, although there is a peak age in young adults. It rarely causes drop metastases. 9
PTPR (WHO 2016, grade II or III) is a neuro-epithelial neoplasm arising from ependymocytes of the subcommissular organ. It affects a wide range of ages from 5 to 65 years old. Drop metastases arise in 7% of the cases.13
The symptoms are related to tumor local invasion and/or compression of adjacent structures, depending on the size and aggressiveness of the mass.
Compression of the midbrain anteriorly with obstruction of the aqueduct of Sylvius leads to obstructive hydrocephalus and symptoms of increased intracranial pressure. Compression of the tectal plate causes visual problems (Parinaud syndrome).11 Infiltration of the thalamus may lead to loss of sensation and weakness on one side of the body. When the tumor expands into the suprasellar region, symptoms related to the hypothalamus may occur. Precocious puberty is a result of elevated HCG.
CT and MRI are critical for the evaluation of the location, size and shape of the pineal tumor. The imaging findings are not specific.14 The differential diagnosis is difficult and often a biopsy is required to determine the histological type. However, there are crucial signs that could narrow the differential diagnosis. In the presence of calcifications, the pattern of involvement is helpful. Germinomas tend to engulf the calcifications, in contrast to pineal parenchymal tumors, where calcifications are distributed. Additionally, some tumors, like pineoblastomas, infiltrate adjacent structures, the third ventricle and the basal cisterns, whereas others like germinoma exhibit edema.
A CT scan of the brain constitutes the first imaging method and can be beneficial for the assessment of the pineal region and the presence of hydrocephalus, calcifications and hemorrhage, although it should be avoided in children due to radiation.
MRI of the brain is considered the gold standard method for the evaluation of the CNS. This method is superior to CT due to the absence of radiation and its high sensitivity, the ability to illustrate anatomical details of the brain and the excellent separation of gray and white matter. MRI improves the distinction between benign from malignant tumors and the differentiation of true pineal masses from parapineal with invasion to the gland. The routine protocol consists of T1, T2, Fluid-attenuated inversion recovery (FLAIR) and Diffusionweighted imaging (DWI) in addition to Susceptibility-weighted imaging (SWI)/Gradient echo sequences (GRE) for the detection of calcifications and hemorrhage. The use of gadolinium (Gd) in axial, coronal and sagittal planes provides information valuable to the treatment planning and enables the evaluation of how welldefined the mass is. MRI determines the site of the origin, the presence of calcifications, hemorrhage, fatty tissue or cystic components and the enhancement of the lesion, features that are crucial for the differential diagnosis. Regarding the differentiation of pineal and parapineal masses, the internal cerebral veins, the tectum of the midbrain, the superior aspect of the cerebellar vermis and the posterior aspect of the tentorial incisures should be examined thoroughly.
The imaging characteristics of pineal germinoma are not specific and include a well-circumscribed, ovoid or lobulated, relatively homogenous mass, that overwhelms the pineal gland. The signal on T1 and T2 WI is variable, most commonly slightly hyperintense on both sequences. They may demonstrate cystic or hemorrhagic components and a tendency to invade the adjacent tissues, surrounded by edema. Markedly enhancement may be seen on MR, due to their cellularity, either homogenous or inhomogeneous with regard to their content (Figure 1). The differential diagnosis between germinoma and pineal parenchymal tumors is not accurate. A helpful sign could be the engulfment of the normal physiologic calcification, while pineal parenchymal tumors appear exploded.15 If the imaging findings are present in a young male, the diagnosis is in favor of germinoma. Additionally, a hypointensity on T2WI may also be helpful in the differential diagnosis of a germinoma from a pineal parenchymal tumor.16,17 Dumrongpisutiku et al.12,14,18,19 reported that the signal on T1 and T2 WI does not illustrate significant differences between germinomas and pineal parenchymal tumors and that most of the pineal region tumors show heterogeneous enhancement, which is in agreement with other studies.
Teratoma is composed of all three germ cell lines presenting a heterogeneous appearance. The majority of non-germinomatous germ cell tumors contain fat, calcifications most often clump like, hemorrhage, teeth, hair, cystic and solid components. 20 Their signals on MR sequences are not specific and present a variable enhancement of the solid tissue. Hydrocephalus occurs frequently. Detection of a midline heterogeneous mass in a child should suggest the diagnosis of a teratoma.
The rare germ cell tumors have no specific imaging characteristics and may demonstrate imaging features similar to other germ cell or primary pineal tumors.21 These lesions may contain hemorrhage, fat, or calcifications, resulting in T1 shortening. GRE sequences should be obtained in order to demonstrate and differentiate these elements. MRI can also be helpful in the evaluation of pineal parenchymal tumors. On MR, they are usually iso- to hypointense on T1WI, while on T2WI the appearance is variable, with the majority being iso- to hyperintense to gray matter.
Pineoblastoma, a highly aggressive tumor may contain hemorrhagic, necrotic or cystic foci. MRI can identify the tumor and the intrusion of the adjacent tissue but also the presence of leptomeningeal and subependymal metastases. These tumors are ill-defined because of their tendency to infiltrate the surrounding structures. On T1 WI, in the absence of hemorrhage, they have iso- or lower signal compared to the adjacent brain parenchyma. On T2 WI, the majority is isointense, unless a cystic component produces a high signal. These tumors exhibit restriction on DWI and intense, inhomogeneous enhancement after Gd administration. Central necrotic elements must be differentiated from cystic by the administration of Gd, whereas the differentiation from a pineal cyst may be difficult. 22 Pineocytomas are well defined lesions with solid, enhanced components. Cystic or hemorrhagic areas can be demonstrated, thus the signal on T1 and T2 WI is variable. The well defined contours are helpful to the differential diagnosis in order to distinguish them from pineoblastomas (Figure 2).20 A calcified pineal mass in a female is more likely to represent a pineocytoma. Regarding PTPR, although the presence of high signal on T1WI is a relatively specific finding, variable signal intensity on T1WI and hyperintensity on T2WI are presented. According to Chang et al the presence of high signal on T1WI may be related to the concentration of protein and glycoprotein content in the cystic regions and this may be a common imaging finding for papillary tumors.23
Intradural extramedullary Metastases
Spinal metastases are classified as extradural, intradural extramedullary and intradural intramedullary lesions. The majority are extradural with an incidence of up to 95% while intradural extramedullary metastases account for up to 5-6% of spinal metastases. Intramedullary metastases are extremely rare, accounting for 0, 5-1%.24
Drop metastasis is a term for intradural extramedullary metastatic lesions of the spine that result from subarachnoid spread of a primary brain tumor. Those metastases are identified inside the dura but always outside the spinal cord. They arise from pineal tumors, ependymomas, medulloblastomas, primitive neuroectodermal tumors (PNET), glioblastomas multiform, anaplastic astrocytomas and oligodendrogliomas. The most frequent tumors that cause drop metastases in children are medulloblastomas, ependymomas, germinomas and pineoblastomas and less commonly choroid plexus neoplasms and teratomas. Drop metastases occur in 5% to 30% of children, either early, at the time of diagnosis of a brain tumor, or during the follow-up. Medulloblastoma is the most common source, accounting for half of the patients with drop metastases.25 It is mainly diagnosed in children under 10 years of age, with a second smaller peak between 15 and 35 years old. Glioblastoma multiform is the second most common tumor with an incidence of 1% of cases and in 15% of all patients with drop metastases.25,26
The two most common pineal tumors causing drop metastases are germinomas and pineoblastomas.
Pineocytomas are rarely associated with drop metastases. CSF spreading is likely to occur more often in high-grade (36%) than in low-grade (7%) PPTID.12,29 It has also been reported that PTPR may cause drop metastases in 7% of the cases.13
Pineal metastasis is uncommon, affecting 5% of patients with pineal tumors who underwent surgery. Lung cancer is the most common cause, however breast, kidney and gastrointestinal tract are also related. Leptomeningeal spreading is common and is present in 67% of patients.30
Some brain tumors invade the leptomeninges or ependymal and seed the subarachnoid space with cell dispersion through the CSF into the spinal canal. Another possible way is iatrogenic dispersion during a resection of a brain mass.33,34
The spread of the malignant cells through the spinal canal follows the pathway of the CSF, which runs along the dorsal side of the spinal cord.35 As a result the lesions are mostly detected posteriorly. The nerve root sheaths, cauda equine and the fundus of the thecal sac may also be involved.36
The majority of the patients will suffer from back pain at the beginning, while others may have no symptoms at the time of diagnosis. Often pain is of a severe, burning nature.31 Neurologic symptoms and mainly lower back or radicular pain will occur after the onset of pain. Subsequently, motor weakness, paraesthesias of lower extremities, gait disturbance and cauda equina syndrome may occur. One third of the patients will present anal sphincter disturbance.37
Drop metastases may occur at the time of diagnosis of a pineal tumor affecting surgical planning or they may occur during the treatment without recurrence of the primary tumor. Their detection is vital because survival is poor if early treatment of tumor dissemination is not performed. Drop metastases are mainly located at the lumbosacral level followed by the thoracic location but the whole neuroaxis should be investigated.
Imaging includes CT and MRI. CT is considered a poor method for the assessment of possible metastatic disease. Even though it can evaluate the spine, it may often appear normal in the pre and post contrast images.
MRI has the ability to detect drop metastases as well as to define the relationship between the lesion and the cord, to identify the presence of large feeding/draining vessels and to yield pre-operative diagnosis. 32,38-40
The MR protocol includes T1, T2 and fat suppressed WI at least in sagittal and axial planes with Gd administration. T1WI with Gd is the most sensitive sequence, especially with fat suppression (Figure 3).
Typical imaging characteristics include nodular lesions that are isointense to the spinal cord on T1WI with intense enhancement after Gd administration. Cord edema may be present in more extensive disease, especially if there is an intramedullary component on T2 images. The detection of the nodules is more difficult on T2 WI and they are recognized by a slightly lower signal compared to CSF. T2 Fat suppressed sequences are very useful, since cord edema can be more obvious than on T2 WI.
When a solitary intradural extramedullary metastasis is detected on a nerve root, the differential diagnosis from a nerve sheath tumor is problematic.41
The nerve roots may show thickness and enrichment with Gd as well as the cauda equina. If drop metastases are present in the cauda equina, nodules can be detected as small isointense lesions, with considerable contrast enhancement.42 Occasionally, diffuse enhancement may be seen in the thecal sac. In patients with leptomeningeal drop metastases or leptomeningeal carcinomatosis from non-cranial tumors, the appearance of the spinal canal mimics an effect of sugar coating on post-contrast images (Figure 4).43,44 In some cases drop metastases may lead to carcinomatous meningitis or dural involvement due to inflammation, with the presence of thickened, enhanced leptomeninges. On the T1 post-Gd images, nodules and/or plaques may be identified as the tumor develops further (Figure 5). In carcinomatous arachnoiditis the roots of the cauda equina appear mottled, ill-defined and sometimes they may have an asymmetric distribution within the thecal sac. The involvement of the spinal ganglion is crucial for the detection of arachnoiditis due to carcinomatosis.
About 90% of spinal lesions that affect either the spinal canal or the vertebrae are considered to be metastatic. The most common intradural extramedullary lesions in children are drop metastases.45,46 Extra-cranial primary neoplasms are the second source of intradural extramedullary metastases, presenting the main cause of these metastases in adults. If MRI identifies intradural extramedullary nodules with contrast enhancement then breast, lung cancer or melanoma should be excluded in adults (Figure 6). Other tumors associated are neuroblastoma, retinoblastoma and rhabdomyosarcoma. 47 Leukemia and spinal lymphoma have a high rate of leptomeningeal infiltration.48,49
Approximately 35% of intradural extramedullary lesions concern nerve sheath tumors including spinal schwannomas and neurofibromas which is often difficult to be distinguished because of their similar appearance.26 They exhibit low T1 and high T2 signal with contrast enhancement and adjacent bone remodeling. Spinal schwannomas usually demonstrate more heterogeneous intensity, due to hemorrhagic and cystic components, vascular changes and fatty degeneration.45 They may have a dumbbell shape as a result of their extradural and intradural extension through the intravertebral foramen. Neurofibromas and rarely schwannomas may present a central area of low signal on T2 that is likely to represent a collagenous stroma (target sign).50
Spinal meningiomas, most commonly detected in the thoracic spine, are the second most common intradural intramedullary masses in 20% of the cases. They are iso- to hypointense on T1 WI, hyperintense on T2 WI, homogenous enhanced.51 The presence of the dural tail sign and the broad attachment of the lesion with the dura are not pathognomonic for this type of tumor.
The evaluation of the size and number of the lesions are helpful to the differential diagnosis. Nerve sheath tumors and meningiomas are larger in size than intradural extramedullary metastases.51 Moreover, they are more often solitary and mainly occur in adults unless they are associated with neurofibromatosis (NF). Multiple menigiomas and schwannomas are related to NF2, whereas multiple neurofibromas correlate with NF1.
Paragangliomas are benign hypervascular tumors affecting patients between 13 and 70 years old.52 They are rarely located in the spinal canal, more commonly to the cauda equina. They show a high signal on T2WI and contrast enhancement. Discrete flow voids may occur in this area due to the hypervascularity of the lesion as well as a rim of hemosiderin on T2 WI.45
Myxopapillary ependymomas represent about 50% of spinal ependymomas in adults but less than 13% in children.53,54 On MRI the lesions show intermediate signal or less often high on T1 WI, due to mucinous component and high signal on T2 WI.55 In the presence of hemorrhagic components, low signal on T2 WI may be present. The lesion is enhanced homogeneously depending on the extent of the hemorrhage.55,56 Myxopapillary ependymomas may grow so much that they might expand throughout the spinal canal with scalloping of the vertebral bodies.
If there is pachymeningitis with diffuse thickening and enhancement of the meninges, carcinomatosis, infection or inflammation of the leptomeninges should be taken into consideration.
The sugar coating pattern on MRI imaging is seen in patients with intradural intramedullary metastases.
The differential diagnosis includes infectious meningitis especially in the immunocompromised patients, post infectious diseases like Guillain-Barré and inflammatory arachnoiditis often postoperatively.
Regarding inflammatory arachnoiditis there is usually a history of operation combined with specific MRI findings. Irregular thickening and clumping of nerve roots result in an empty sac sign on T2 WI, usually at the lumbar spine.
CSF laboratory examination is important for the diagnosis of infectious diseases. The clinical history of recent viral infection is typical for the Guillain-Barré syndrome. In this syndrome MRI findings are detected in the lower spine with thickening and enhancement of the conus medullaris and nerve roots of the cauda equina.
It is important not to confuse blood in the subarachnoid space postoperatively with leptomeningeal metastases. Subarachnoid or subdural blood may show high signal on T1 WI and illustrate enhancement of the leptomeninges as well. Comparison with preoperative spine MRI is useful.
The therapeutic plan of pineal tumors depends on the histological type, the size and the presence of drop metastases.
Surgery in the pineal region is anatomically difficult and is not usually possible to completely remove the tumor. This method is usually helpful for dealing with complications like obstructive hydrocephalus and the identification of the tumor’s type.
Radiotherapy and chemotherapy play an important role in the treatment of pineal tumors.57-59
In the presence of drop metastases, the treatment plan includes neurosurgery, radiotherapy and the grant of steroids, depend on the site and the number of the lesions. Systemic and intrathecal chemotherapy may also relieve symptoms.
It is extremely significant for the prognosis of patients with pineal tumors to accurately identify the presence of drop metastases. The prognosis of patients with infiltration of the neuroaxis is extremely poor and therapy is palliative with a median patient survival two to three months.
Hsieh et al. concluded that drop metastases found at presentation seem not to be a prognostic factor, though late drop metastases found during the follow-up reflect the relative resistance of adjuvant therapy and may be viewed as a possible poor prognostic factor.60
MRI is the gold standard method for the evaluation of pineal tumors and the detection of intradural extramedullary metastases guiding the therapeutic planning. MRI should be performed early at the diagnosis of the pineal tumors and during the followup providing crucial information about the stage and possible recurrence of the disease.