Pineocytoma

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]Associate Editor(s)-in-Chief: Sujit Routray, M.D. [2]

Synonyms and keywords: Pineocytomas; Pinealocytoma; Pinealocytomas; PC; Pineal gland tumor; Brain tumor

Overview

Pineocytoma is a benign, slowly growing pineal parenchymal tumor. The pineal gland, in the brain secretes melatonin which regulates sleep cycle . Pineocytomas most often occur in adults as a solid mass, although they may appear to have fluid-filled (cystic) spaces on images of the brain. Signs and symptoms of pineocytomas include headaches, nausea, , vision abnormalities, and Parinaud syndrome. Pineocytomas are usually slow-growing and rarely spread to other parts of the body. Treatment includes surgery to remove the pineocytoma; most of these tumors do not regrow (recur) after surgery.

Classification

The 2007 WHO classification of central nervous system tumors divides pineal gland tumors into four groups [16]:

• Pineocytoma (grade I)
• Pineal parenchymal tumors of intermediate differentiation (grade II or III)
• Papillary tumor of the pineal region (grade II or III)
• Pineoblastoma (grade IV)

Pathophysiology

Normal Anatomy

• The pineal gland is a small reddish-brown structure that derives its name from its pinecone-like shape.
• The pineal ranges in size from 10 to 14 mm; it is located in the midline, above the tentorium and superior colliculi and below the splenium of the corpus callosum and the vein of Galen, and is attached to the superior aspect of the posterior border of the third ventricle.

Embryology

• Pineal gland develops as a diverticulum in the diencephalic roof of the third ventricle during the second month of gestation.
• The mature gland is suspended from the pineal stalk from the posterior roof of the third ventricle.
• The pineal secretes melatonin, which is involved in diurnal rhythms.

Gross Pathology

On gross pathology, pineocytoma is characterized by solid, sometimes with focal areas of cystic change, gray, well-circumscribed mass with or without hemorrhage.

Microscopic Pathology

On microscopic histopathological analysis, pineocytoma is characterized by:

• Cytologically benign cells (uniform size of nuclei, regular nuclear membrane, light chromatin)
• Pineocytomatous/neurocytic rosette, which is an irregular circular/flower-like arrangement of cells with a large meshwork of fibers (neuropil) at the centre

According to the WHO classification of tumors of the central nervous system, pineocytoma is classified into a WHO grade I tumor.

Immunohistochemistry

Pineocytoma is demonstrated by positivity to tumor markers such as:

• Synaptophysin
• Neuron-specific enolase
• GFAP
• Chromogranin A
• PLAP
• Ki-67
• Beta tubulin III

Gallery

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  _{Intermediate magnification micrograph of a pineocytoma. HPS stain.}

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  _{High magnification micrograph of a pineocytoma. HPS stain.}

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  _{Very high magnification micrograph of a pineocytoma. HPS stain.}

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  _{The tumor cells are diffusely positive for synaptophysin and neurofilament.}

• 

  _{Positivity to Ki-67. The Ki-67 index is 2-3%.}

Differentiating Pineocytoma from other Diseases

Pineocytoma must be differentiated from:

• Pineal parenchymal tumor with intermediate differentiation
• Papillary tumor of the pineal region
• Pineoblastoma
• Pineal germinoma
• Pineal embryonal carcinoma
• Pineal choriocarcinoma
• Pineal yolk sac carcinoma (endodermal sinus tumor)
• Pineal teratoma
• Pineal cyst
• Astrocytoma of the pineal gland
• Meningioma near pineal gland
• Pineal metastasis
• Cavernoma in pineal region
• Aneurysm in pineal region

Tumors	Grade	Pathalogic Features	5-year survival	Cerebrospinal fluid (CSF) dissemination	Imaging
					CT	MRI
Pineocytoma	Grade I lesion	Small, uniform, mature cells that resemble pineocytes Lobular architecture and pineocytomatous rosettes	86%–100%	Rare	Well demarcated, usually less than 3 cm, and iso- to hyperattenuating.	Hypo- to isointense on T1-weighted images and hyperintense on T2-weighted images.
Pineal Parenchymal Tumor of Intermediate Differentiation	Grade II or III	Gross inspection, PPTID is similar in appearance to pineocytoma. It is a well-circumscribed lesion without evidence of necrosis. Histologic evaluation reveals diffuse sheets of uniform cells and the formation of small rosettes, with features intermediate between those of pineocytoma and those of pineoblastoma. Low to moderate levels of mitotic activity and nuclear atypia are seen.	39%–74%	Rare	No specific imaging findings	No specific imaging findings Demonstrate high signal intensity on T2-weighted images and enhance on postcontrast images Cystic areas may also be seen
Pineoblastoma	Grade IV	Pineo-blastomas are highly cellular embryonal neoplasms that resemble other primitive neuroectodermal neoplasms of the central nervous system. Cells have scant cytoplasm and are arranged in diffuse sheets. Homer-Wright rosettes (neuroblastic differentiation) or Flexner-Wintersteiner rosettes (retinoblastic differentiation) may be seen, and hemorrhage or necrosis may be present. Infiltration into adjacent structures and craniospinal dissemination commonly occur	58%	Most common cause of the death	Lobulated, typically hyperattenuating mass, an appearance that reflects its highly cellular histologic features.	Ill-defined enhancing pineal mass with resultant hydrocephalus
Papillary Tumor of the Pineal Region	Grade II or III	PTPRs are well-circumscribed lesions that can measure up to 5 cm and may have a cystic component. At histologic evaluation, they demonstrate an epithelial-like growth pattern, papillary features, rosettes, and perivascular pseudorosettes. The immunohistochemical findings help differentiate PTPR from other lesions in the pineal region, especially ependymoma and choroid plexus papilloma.	73%	75% times		Well-circumscribed lesions with variable signal intensity on T1-weighted images, high signal intensity on T2-weighted images, and enhancement on postcontrast images. Cystic areas are commonly present. Hyperintensity on T1-weighted images has been described, which is hypothesized to be related to secretory inclusions containing protein or glycoprotein.
Germinoma	Grade II	Account for 1%–2% of all cranial neoplasms 65% of intracranial germinomas occur in the pineal region	>79%	The possibility of CSF seeding necessitates imaging evaluation of the entire neuroaxis	Sharply circumscribed, hyperattenuating mass that engulfs the pineal calcifications	Demonstrates a solid mass that may have cystic components. Germinomas are iso- to hyperintense to gray matter on T1- and T2-weighted images Avid, homogeneous enhancement on postcontrast images
Teratoma	Grade III	Mature teratoma reveals a lobulated neoplasm with a complex mixture of adult-type tissues from all three embryonic germ layers. Skin and skin appendages may be seen due to the ectodermal component. The mesoderm contributes to the presence of cartilage, bone, fat, and smooth and skeletal muscle. Respiratory or enteric epithelium arises from the endodermal component. Immature teratomas contain incompletely differentiated tissue elements that resemble fetal tissue.			Multiloculated, lobulated lesion with foci of fat attenuation, calcification, and cystic regions	T1-weighted MR images may show foci of T1 shortening due to fat and variable signal intensity related to calcification. On T2-weighted images, the soft-tissue component is iso- to hypointense.
Pineal Cyst	Grade II	Pineal cysts occur in all age ranges but are most predominant in adults 40–49 years of age; studies demonstrate a female predominance. Their origin is debated, with some suggesting they result from degenerative changes in the gland. These lesions are typically asymptomatic and are usually 2–15 mm in size. Follow-up studies have indicated that these lesions remain stable in size over time. When they exceed 15 mm, patients may become symptomatic, typically with headache or visual changes. Intracystic hemorrhage (“pineal apoplexy”) and acute hydrocephalus rarely occur; resultant death has been reported	75% of pineal cysts remained stable during a period of 0.5–9.1 years.	Rare		Round or oval, thin-walled, and well-circumscribed. They typically demonstrate signal intensity similar to that of CSF on T1- and T2-weighted images
Epidermoid and Dermoid Cysts		The wall of epidermoid cysts is composed of simple stratified squamous epithelium, and the cyst contents consist of layers of keratinaceous debris, which impart a “pearly” appearance to the gross specimen. Dermoid cysts contain dermal appendages (hair follicles, sweat glands. Both lesions slowly expand over time and rupture can result in chemical meningitis, which may be fatal.			Epidermoid cysts have low attenuation, similar to that of CSF. Dermoid cysts have a more variable appearance, and areas of low attenuation may be seen due to a lipid component—not due to fat, which is of mesodermal origin. Peripheral calcifications may be seen in both lesions.	Epidermoid cysts are hypointense on T1-weighted images and hyperintense on T2-weighted images, with signal intensity similar to that of CSF. They insinuate into adjacent structures and encase nerves and blood vessels, making resection difficult.
Astrocytoma	Grade I II III IV	Uncommon. They derive from stromal astrocytes In the pineal region they arise from the splenium of the corpus callosum, the thalamus, or the tectum of the midbrain. Rarely, they may arise from the neuronal elements within the pineal gland.				Bulbous enlargement of the tectal plate is noted. The lesion is typically isointense on T1-weighted images Hyperintense on T2-weighted images with no to minimal enhancement on postcontrast images
Lipoma		Abnormal differentiation of the meninx primitiva, which is the undifferentiated mesenchyme that surrounds the developing brain and normally develops into the leptomeninges and subarachnoid space. Lipomas represent malformations and not neoplasms. Blood vessels and nerves course through them, making resection difficult if required.			low attenuation, consistent with fat	hyperintense on T1-weighted images with saturation on fat-saturated images

Epidemiology

Prevalence

• Pineocytoma constitutes approximately 45% of the pineal parenchymal tumors.
• Pineocytoma constitutes approximately 0.4 - 1% of the intracranial neoplasms.

Age

• Pineocytoma is a rare disease that tends to affect all age groups, most commonly in the second decade of life.
• Pineal tumors are more common in children aged 1 to 12 years where these constitute about 3 percent of brain tumors [2].

Gender

• Pineal tumors are substantially more common in males.
• In those with germ cell tumors, the male predominance was approximately 12:1.

Demographics

• In Europe and North America, pineal tumors account for less than 1 percent of all primary brain tumors.

Race

• Pineal tumors are more common in Asian countries than in Western countries.
• This increased frequency is due largely to an increase in germ cell tumors, which comprise 70 to 80 percent of all pineal region tumors in Japan and Korea.

Natural History, Complication and Prognosis

Natural History

If left untreated, patients with pineocytoma may progress to develop seizures, obstructive hydrocephalus, local recurrence, and CSF metastasis.

Complications

Common complications of pineocytoma include:

• Obstructive hydrocephalus
• Local recurrence
• CSF metastasis
• Distant metastasis (most commonly, lung)

Prognosis

• Prognosis is generally excellent, and the 5-year survival rate of patients with pineocytoma is approximately 86%.
• Pineocytoma has the most favorable prognosis among all the pineal gland tumors.
• Clark et al. after performing a systematic review of the literature reported that the 1- and 5-year progression free survival (PFS) rates for patients that underwent resection versus the biopsy group were 97% and 90%, and 89% and 75% respectively. The 1- and 5-year PFS rates for the gross total resection group versus the group undergoing subtotal resection combined with radiation therapy were 100% and 94%, and 100% and 84% respectively.

History and Symptoms

History

When evaluating a patient for pineocytoma, you should take a detailed history of the presenting symptom (onset, duration, and progression), other associated symptoms, and a thorough family and past medical history review.

Symptoms

• The clinical presentation of pineocytoma is mainly from the obstructive hydrocephalus secondary to compression of the tectum of the midbrain and obstruction of the aqueduct.
  • Pineal tumors cause neurologic dysfunction by direct invasion, compression, or obstruction of cerebrospinal fluid (CSF) flow.
  • The rate of tumor growth determines the rapidity of symptom onset and is an important prognostic factor.
• Pineal gland tumors share some common clinical and radiographic features based upon their anatomic location. Symptoms of pineocytoma include:

• Hydrocephalus is common, manifested by headaches, lethargy, and signs of increased intracranial pressure.
• Progressive local tumor growth may result in cranial neuropathies or hypothalamic dysfunction.
  • Sleepiness
  • Irritability
  • Personality changes
  • Double vision
  • Trouble coordinating motor movements
  • Difficulty walking
  • Slowed growth

Symtpoms	Signs
Headaches	Papilledema
Vision abnormalities	Ataxia
Nausea and vomiting	Loss of upward gaze
Impaired ambulation	Tremor
	Altered pupillary reflexes
	Hyperactive deep tendon reflexes

Physical Examination

Compression of the superior colliculi can lead to a characteristic gaze palsy, known as Parinaud syndrome. Common physical examination findings of pineocytoma include:

HEENT

• Bulging soft spots (fontanelles)
• Eyes that are constantly looking down (sunsetting sign)
• Deficiency in upward-gaze
• Pupillary light-near dissociation (pupils respond to near stimuli but not light)
• Convergence-retraction nystagmus

Neurological

• Mental retardation
• Muscle spasms
• Loss of bladder control
• Ataxia

CT

• Head CT scan may be diagnostic of pineocytoma.
• Findings on CT scan suggestive of pineocytoma include a mass of intermediate density similar to the adjacent brain with peripheral calcifications.

Gallery

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  _{Different patterns of pineal calcification: Exploded calcification of tumors of pineal cell origin and engulfed calcification by germinomas.}

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  _{Single image following biopsy and third ventriculostomy demonstrates a pineal region soft tissue mass. A small amount of blood is seen in the occipital horn on the right. Ventricles remain dilated.}

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  _{A 14 X 13 mm (axial) soft tissue density mass in the pineal region with eccentric peripheral calcification demonstrated. The ventricles are prominent, out of keeping with the degree of sulcal prominence, indicating mild to moderate obstructive hydrocephalus due to the lesion partially obstructing the upper margin of the cerebral aqueduct. Periventricular hypoattenuation is in keeping with chronic small vessel ischaemia +/- transependymal CSF accumulation.}

MRI

• Brain MRI may be diagnostic of pineocytoma.
• Features on MRI suggestive of pineocytoma include:

MRI component	Findings
T1	Isointense to brain parenchyma
T2	Solid components are isointense to brain parenchyma Areas of cystic change Sometimes the majority of the tumor is cystic
T1 with gadolinium contrast	Solid components vividly enhance

Gallery

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  _{A large and ill-defined mass is present in the region of the pineal gland, demonstrating contrast enhancement.}

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  _{Axial T2 demonstrating a circular mass centered in pineal region measures 12 x 11 x 9 mm and demonstrates homogeneous enhancement (on volumetric sequence for stereotaxis), peripheral calcification, and diffusion restriction. It has mass effect on the adjacent structures with stenosis of the cerebral aqueduct (some flow still present on cine imaging) and associated non-communicating hydrocephalus affecting the lateral ventricles and 3rd ventricle. Foramina of Monroe are patent. No other suspicious enhancing lesion, including of the leptomeninges. No suprasellar/sellar mass in non-dedicated study.}

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  _{T2 MRI image demonstrating a well circumscribed mass is located in the region of the pineal gland. It is a little heterogeneous with multiple small regions of cyst formation (on T2) most marked anteriorly, probably at the site of biopsy.}

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  _{Axial T1 with contrast demonstrating a large enhancing mass is present in the pineal region compressing the tectum and resulting in obstructive hydrocephalus.}

Treatment

• The mainstay of therapy for pineocytoma is surgery (gross total or subtotal resection).
• The treatment of PPTs must be guided by the histologic subtype.

Management Options of Penial Gland tumors
CSF diversion	The optimal surgical strategy to treat acute hydrocephalus in patients with pineal tumors is uncertain. CSF diversion (ventriculoperitoneal [VP] shunt or third ventriculostomy may be necessary in symptomatic patients, although debulking surgery may obviate the need for this procedure When CSF diversion is necessary, endoscopic third ventriculostomy can be carried out at the same time as the biopsy and is preferred over VP shunts, which can be complicated by infection, shunt malfunction, subdural hematoma, and rarely, tumor seeding
Surgical resection	Some series report long-term survival with surgery alone, even in patients with pineoblastomas. Indeed, for pineoblastomas, gross total surgical resection appears to correlate with improved survival. Patients with symptomatic recurrent pineocytomas should also be considered for surgical resection of the lesion
Radiation	Postoperative adjuvant RT is frequently (but not universally) recommended, and local control is dose-dependent. The incidence of leptomeningeal recurrence was significantly lower among patients receiving CSI compared with those who did not. The five-year survival rates were 86 and 49 percent for pineocytomas and non-pineocytoma PPTs, respectively. Adjuvant RT is not universally recommended after gross total resection of a pineocytoma
Stereotactic radiosurgery	Stereotactic radiosurgery (SRS) is emerging as a useful treatment alternative for pineocytomas, although experience is limited. The precise radiation fields that are defined by MRI or CT-computerized treatment planning minimize damage to the surrounding brain, and the risks of general anesthesia and craniotomy are avoided. SRS is increasingly being used to treat pineal region tumors, either as an additional therapy after conventional treatments or as a primary treatment. Due to the low rate of side effects, IRS may develop into an attractive alternative to microsurgery in de novo diagnosed pineocytomas. In malignant PPTs, IRS may be routinely applied in a multimodality treatment schedule supplementary to conventional irradiation.
Chemotherapy as part of multimodality therapy	The similarity of pineoblastomas to medulloblastomas in terms of their clinical behavior and tendency for leptomeningeal seeding has led to the use of similar chemotherapy regimens in patients with pineoblastoma as part of a multimodality approach. Chemotherapy has been used to delay radiation therapy in very young children, for whom the long-term neurocognitive and developmental side effects of craniospinal irradiation (CSI) are a major concern. The importance of radiation therapy as a component of the initial treatment of supratentorial primitive neuroectodermal tumors (PNETs) is also supported by the German HIT-SKK87 and HIT-SKK92 protocols, as well as the Canadian pediatric brain tumor protocol

• Successful treatment of pineocytomas requires surgery with or without RT, while the best results with pineoblastomas are seen with multimodality approaches that include chemotherapy.
• The main goal of open surgery on pineocytoma is the complete tumor removal with minimal morbidity, whenever possible. However, even if gross total excision cannot be achieved, establishment of an accurate diagnosis, maximal cytoreduction, and restoration of the CSF pathway may be achieved.
• Radiotherapy administration to subtotally resected tumor is not associated with an increase in either tumor control or survival.
• Stereotactically guided iodine-125 seed implantation has been proposed as a potential alternative to microsurgery in de novo diagnosed pineocytomas, since it was proven efficient and safe.
• Patients with pineocytoma will develop hydrocephalus in majority of the cases and they will require CSF diversion. Ventriculo-peritoneal (V-P) shunt placement is a viable option with low morbidity and mortality rate. However, shunt malfunction in this population is as high as 20%. In addition, tumor metastasis through a CSF shunt has been reported. Endoscopic third ventriculostomy (ETVC) is an alternative option, which also permits a biopsy of the tumor in the same procedure. Ahn et al. reported that the biopsy samples, obtained in the lateral ventricle or pineal region, were more favorable towards a successful diagnosis than those in the thalamus or tectal region. Neuroendoscopic biopsy procedures have been proven safe with low complication rates.

References

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