Intracranial Germ Cell and Pineal Tumors
BACKGROUND
What are the 2 broad categories of germ cell tumors?
Gonadal and extragonadal
Pineal tumors represent what % of adult and children’s tumors?
Pediatric: 5%
Adult: 1%
Germ cell tumors represent what % of pediatric and adult brain tumors?
Pediatric: 3%–11% (more frequent in Japan and Asia)
Adult: 1%
What would a “germinoma” of the testicles or ovaries be referred to?
Germinoma is referred to as seminoma in the testicles and dysgerminoma in the ovaries.
What are the 3 subtypes of extragonadal germ cell tumors? Which are more common in adults vs. children?
Sacrococcygeal, retroperitoneal, and intracranial. In adults, most common sites are ant mediastinum, retroperitoneum, pineal/suprasellar areas. In infants or children, intracranial and sacrococcygeal teratomas are more common.
What are the 2 subtypes of intracranial germ cell tumors? Which has a more favorable prognosis? Which is more common?
Germinoma and nongerminomatous germ cell tumor (NGGCT). Germinoma has a more favorable prognosis and requires less-intensive therapy. Germinomas are more common (two-thirds of all intracranial germ cell tumors).
What are 4 subtypes of intracranial NGGCTs?
Endodermal sinus tumor (yolk sac, elevated AFP), choriocarcinoma (elevated β-HCG), teratoma (immature and mature), embryonal (elevated β-HCG and AFP), and mixed (25% of NGGCT).
What are the median age at Dx and the sex/race predilection for germinomas?
10–12 yrs, males > females (2–3:1), Asian > white (4% vs. 1% pediatric CNS tumors in Asia vs. the U.S.)
Where do the majority of intracranial germinomas and NGGCTs arise?
Midline proximal 3rd ventricular structures: two-thirds pineal and one-third suprasellar. Other sites include basal ganglia, thalamus, cerebral hemisphere, and cerebellum. 5%–10% present with both pineal and suprasellar tumors, may be bifocal rather than metastatic, and are usually pure germinomas.
What % of germinomas have CSF dissemination at Dx?
10%–15% (50% of pineoblastomas have leptomeningeal dissemination)
What is the probability of spinal failure in pts with various types of pineal-based tumors without evidence of spinal seeding at Dx?
Mature and immature teratoma: 0% (0 of 16)
Mixed NGGCT: 4% (1 of 24)
Other NGGCT: 39% (3 of 9) (teratomas with malignant transformation and yolk sac tumors)
Germinoma: 17% (8 of 46)
Pineocytoma: 0% (0 of 7)
Pineal parenchymal tumor (PPT), pineoblastoma, or PPT of intermediate differentiation: 8 of 14 (57%)
Pineoblastoma and NGGCT have the highest propensity for CSF dissemination.
(Schild SE et al., Cancer 1996)
What is the typical presentation of a tumor in the pineal region?
↑ ICP (due to obstructive hydrocephalus, causing, n/v, papilledema, lethargy, somnolence); Parinaud syndrome (decreased upward gaze, accommodates but abnl light response); endocrinopathies rare but diabetes insipidus (DI) sometimes observed.
Pressure/mass effect on what anatomic structure causes Parinaud syndrome?
Pressure/mass effect on the superior colliculus causes Parinaud syndrome.
How do pts with suprasellar masses present?
Triad of visual difficulties (bitemporal hemianopsia), DI, and precocious or delayed/abnl sexual development. Other aspects of hypothalamic/pituitary dysfunction possible, including GH deficiency, hypothyroidism, and adrenal insufficiency.
WORKUP/STAGING
What is the DDx for a pediatric brain tumor in the pineal region?
Pineoblastoma, pineocytoma, PPT of intermediate differentiation, germinoma, NGGCT, glioma, meningioma, lymphoma, benign cyst, Langerhans cell histiocytosis, hamartoma; most are germ cell tumors.
What is the DDx for a pediatric brain tumor in the suprasellar region?
Germinoma, NGGCT, craniopharyngioma, pituitary adenoma, meningioma, glioma, aneurysm, infection, metastases
What is the workup for a suspected germ cell tumor?
Suspected germ cell tumor workup: H&P (esp CNs, funduscopic exam), MRI brain/spine, basic labs, serum AFP/β–HCG, CSF AFP/β-HCG (more sensitive than serum), and CSF cytology
What AFP levels exclude the Dx of a germinoma?
An AFP >10 ng/mL excludes the Dx of pure germinoma.
What β-HCG levels exclude the Dx of germinoma?
None are truly exclusive, but if the β-HCG is >50 ng/mL, then it probably is not a germinoma. Very high levels are consistent with choriocarcinoma.
What stain definitively confirms the Dx of a germinoma?
Placental alkaline phosphatase staining confirms the Dx of germinoma.
What is the role of surgery in Dx of GCT?
If AFP and β-HCG are normal, surgery can distinguish pure germinoma or mature teratoma from other benign or malignant lesions. If β-HCG is elevated but normal AFP, surgery can distinguish β-HCG secreting germinoma from immature teratoma or choriocarcinoma (i.e., NGGCT).
What are the typical MRI findings of pure germinoma? Are there any distinctions on imaging from NGGCTs?
Homogeneous or heterogeneous pattern, hypointense T1, hyperintense T2, +Ca, cysts. These are indistinguishable from NGGCTs on imaging.
Historically, how was RT used in the Dx of intracranial germinomas?
Tumors were irradiated with a diagnostic dose of 10–20 Gy. If there was a response, then the Dx was germinoma and RT was continued to a definitive dose of 40–56 Gy. This is no longer done.
What staging system is used for intracranial GCTs M staging?
The medulloblastoma staging (modified Chang) system is used for staging of intracranial GCTs M staging, but usually M0 or M+ (disseminated) is adequate.
TREATMENT/PROGNOSIS
What is the most important prognostic factor in germ cell tumors?
Histology is the most important prognostic factor in germ cell tumors.
What is the prognosis of pure germinomas vs. NGGCTs?
The prognosis is better for germinomas (5-yr PFS >90% vs. 40%–70%, respectively).
Describe 2 Tx paradigms for localized pure germinomas.
Tx paradigms for localized germinoma:
1. Definitive RT
or
2. Neoadj chemo → lower dose RT (experimental protocol)
Describe the definitive RT technique for localized germinoma.
Whole ventricular radiation therapy (WVRT) to 21–24 Gy, boost to primary tumor to 40–45 Gy
For which pineal tumor type is surgery generally not done?
Surgery is generally not done for germinomas, since they are radiosensitive tumors and can lead to morbidity. However, extent of resection is important for NGGCT.
What is the RT technique for disseminated germinoma/CSF spread?
CSI to 24 Gy, gross Dz boost to 45 Gy
Can chemo replace RT in the Tx of pure germinomas?
No. In a large CNS GCT study (Balmaceda C et al., JCO 1996), 45 germinomas were treated with carboplatin/etoposide/bleomycin. 84% had CR, but 48% recurred in 13 mos and 10% of pts died due to Tx toxicity. >90% were salvaged by RT (ifosfamide/carboplatin/etoposide [ICE] × 3 → involved-field radiation therapy [IFRT] of 24 Gy).
What hypothesis is being tested in the current germinoma study ACNS1123?
ACNS1123 is attempting to determine if neoadj chemo can help reduce RT doses in localized germinoma and NGGCT.
Describe the RT technique with neoadj chemo for localized germinoma.
Reduced RT doses: CR to chemo: WVRT to 18 Gy; boost to 30 Gy in 1.5 Gy/day in patients who achieve a CR on chemo on current COG protocol. PR/stable Dz to chemo WVRT to 24Gy +12 Gy boost
In germinoma protocols, what does “occult multifocal germinoma” refer to? What is the boost volume?
Pineal-region tumor and DI. Boost volume is the enhancing tumor (pineal region), infundibular region, and the 3rd ventricle after WVRT.
In ACNS1123, what chemo agents are being tested?
Carboplatin and etoposide are being tested in ACNS1123.
With pre-RT chemo, what are the RT doses in the experimental arm of ACNS1123 for germinoma?
In ACNS1123, the RT doses depend on the chemo response.
Induction chemo, carbo/etoposide × 4 cycles.
If CR, WVRT to 18 Gy + boost to 30 Gy with IFRT alone.
If <CR, 24 Gy whole ventricular irradiation + 12-Gy boost.
What studies showed that even with CR to chemo, IFRT (without WVRT) may not be sufficient?
SIOP CNS GCT96 (Calaminus G et al., Neurooncol, 2013): M0 pts treated with CSI 24 Gy + 16-Gy boost vs. 2 × ICE → IFRT 40 Gy. CRT 5-yr EFS was 85% vs. 91% with RT alone; 5-yr OS was 92% vs. 94%. All CRT failures were within the ventricular system. Conclusion: Suggest inclusion of ventricles in RT fields. Reduced-dose CSI to 24 Gy effective in M+ Dz.
What other evidence demonstrates that involved-field RT may not be sufficient for germinomas?
Rogers SJ et al.: literature review of 788 pts. There was a greater failure rate in focal RT vs. WBRT or WVRT + boost or CSI + boost (23% vs. 4%–8%). The pattern of relapse was mostly isolated spinal (11%), but there was no difference in WVRT vs. CSI in spinal relapse (3% vs. 1%). Conclusion: WVRT + boost should replace CSI. (Lancet Oncol 2005) Similar findings were found in a Seoul study. (Eom KY et al., IJROBP 2008)
What early studies established the feasibility of RT dose reduction?
German MAKEI 83/86/89 studies (from 50 Gy to 34 Gy)
Describe 2 Tx paradigms for NGGCT.
NGGCT Tx paradigms:
1. Induction platinum-based chemo 4–6 cycles → CSI RT 30–36 Gy (lower dose for CR) → boost primary to 50.4–54 Gy; surgery for residual or recurrent Dz
2. Max surgical resection → adj platinum-based chemo; restage; if no neuroaxial involvement, consolidate with IFRT; if +neuroaxial Dz, CSI to 30–36 Gy, boost to 50.4 Gy
When is chemo indicated in the Tx of NGGCTs?
Chemo is always indicated for NGGCTs (influences survival).
What is the Tx paradigm for pineoblastoma?
Pineoblastoma Tx paradigm: treat as high-risk medulloblastoma (CSI 36 Gy + local boost to 54 Gy)
What is the Tx paradigm for pineocytoma?
Pineocytoma Tx paradigm: treat like a low-grade glioma (GTR → observation; STR → consideration of adj RT or observation with Tx at the time of progression [50–54 Gy])
Which study showed that bifocal germinoma can be treated as localized Dz?
Canadian data (Lafay-Cousin L et al., IJROBP 2006): chemo and then limited-field RT (WVRT + boost) resulted in a CR.
TOXICITY
Which recent study showed better QOL with CRT (dose/field reduction) than with RT alone?
Seoul study (Eom KY et al., IJROBP 2008), need for hormonal therapy: RT alone 69% vs. CRT 38% (however, all RT alone pts rcvd CSI)
What is the long-term rate of RT-induced 2nd CNS malignancies? What type is most common?
5%–10%; usually glioblastoma multiforme
What chemo agent should be avoided with brain RT? Why?
6-mercaptopurine. It is associated with high rates of secondary high-grade gliomas.
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