Boris Hristov and Ori Shokek
What are the 2 broad categories of germ cell tumors?
Gonadal and extragonadal
What are the 3 subtypes of extragonadal germ cell tumors?
Sacrococcygeal, retroperitoneal, and intracranial
What are the 2 subtypes of intracranial germ cell tumors?
Germinoma and nongerminomatous germ cell tumor (NGGCT)
What are 4 subtypes of intracranial NGGCTs?
Endodermal sinus tumor (yolk sac), choriocarcinoma, teratoma, and embryonal
Germ cell tumors represent what % of pediatric and adult brain tumors?
1. Pediatric: 3%–11%
2. Adult: 1%
Are germinomas or NGGCTs more common?
Germinomas are more common (two thirds of all intracranial germ cell tumors)
What are the median age at Dx and the gender/race predilection for germinomas?
10–14 yrs, males > females (2:1), 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
What % of germinomas have CSF dissemination at Dx?
15%–20% (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?
1. Mature and immature teratoma: 0% (0/16)
2. Mixed NGGCT: 4% (1/24)
3. Other NGGCT: 39% (3/9)
4. Germinoma: 17% (8/46)
5. Pineocytoma: 0% (0/7)
6. Pineal parenchymal tumor (PPT), pineoblastoma, or PPT of intermediate differentiation: 17% (20/116)
(Schild SE et al., Cancer 1996)
What is the typical presentation of a tumor in the pineal region?
↑ICP, Parinaud syndrome (decreased upward gaze, accommodates but abnl light response)
How do pts with suprasellar masses present?
Triad of visual difficulties, diabetes insipidus (DI), and precocious or delayed/abnl sexual development
Pressure/mass effect on what anatomic structure causes Parinaud syndrome?
Pressure/mass effect on the superior colliculus causes Parinaud syndrome.
What is the DDx for a pediatric brain tumor in the pineal region?
Pineoblastoma, pineocytoma, PPT of intermediate differentiation, germinoma, NGGCT; 80% of pineal-region tumors are germ cell tumors.
What is the workup for a suspected germ cell tumor?
Suspected germ cell tumor workup: H&P (especially CNs, fundoscopy), MRI brain/spine, basic labs, serum AFP/β-HCG, CSF AFP/β-HCG, and CSF cytology
What AFP levels exclude the Dx of a germinoma?
If an AFP is >10 ng/mL, it is not a 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.
What stain definitively confirms the Dx of a germinoma?
Placental alkaline phosphatase staining confirms the Dx of germinoma.
What are the typical MRI findings of pure germinoma? Are there any distinctions on imaging from NGGCTs?
Homogeneous or heterogenous 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 10–30 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 germ cell tumors?
The medulloblastoma staging (modified Chang) system is used for staging of intracranial germ cell tumors.
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 germinomas.
Tx paradigms for localized germinoma:
1. Definitive RT
2. Neoadj chemo → RT (experimental protocol)
Describe the definitive RT technique for localized germinoma.
Whole ventricular radiation therapy (WVRT) to 24 Gy, boost to primary tumor to 45 Gy
For which pineal tumor type is surgery generally not done?
Surgery is generally not done for germinomas.
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 ACNS0232?
ACNS0232 is attempting to determine if neoadj chemo can help reduce RT doses.
Describe the RT technique with neoadj chemo for localized germinoma.
Reduced RT doses: WVRT to 19.8 Gy; boost to 30 Gy
In germinoma protocols, to what does “occult multifocal germinoma” refer?
Pineal-region tumor and DI
For pts with occult multifocal germinoma, what is the boost volume?
Enhancing tumor (pineal region), infundibular region and the 3rd ventricle
In ACNS0232, what chemo agents are being tested?
Carboplatin, cisplatin, and etoposide are being tested in ACNS0232.
With pre-RT chemo, what are the RT doses in the experimental arm of ACNS0232?
1. In ACNS0232, the RT doses depend on the chemo response. Experimental arm: induction chemo, cisplatin/etoposide × 2 cycles.
2. If CR, RT to 30 Gy with IFRT alone.
3. If <CR, 2 additional cycles of chemo → if CR, give WVRT 21 Gy → boost to 30 Gy.
4. If <CR after 2 additional cycles, give standard Tx (M0 or M1).
What studies showed that even with CR to chemo, IFRT (without WVRT) may not be sufficient?
SIOP CNS GCT96 (Calaminus G et al., SIOP Education Book, pp. 109–116): 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.
What other evidence demonstrates that involved-field RT may not be sufficient for germinomas?
Rogers SJ et al., Lancet Oncol 2005: 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%). 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 medulloblastoma (CSI 23–36 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.
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 rcv 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.