Investigation
Germ Cell Tumors (GCT) | Serum/CSF tumor markers | Immunohistochemical tumor markers | Imaging Studies |
Germinomas | HCG, PLAP | PLAP, c-kit and OCT3/4 | CT brain, MRI brain, MRI spine |
Non-germinomatous GCT | ㅤ | ㅤ | ㅤ |
– Teratomas (mature) | – | – | CT brain, MRI brain, MRI spine |
– Teratomas (immature) | HCG, AFP | – | CT brain, MRI brain, MRI spine |
– Embryonal carcinomas | – | CD30 and CK AE1/3 | CT brain, MRI brain, MRI spine |
– Choriocarcinomas | HCG | HCG | CT brain, MRI brain, MRI spine |
– Yolk sac tumors | AFP | AFP | CT brain, MRI brain, MRI spin |
--- config: layout: dagre --- flowchart TB A["Pineal GCT suspected<br>"] --> B["1. Craniospinal MRI<br>2. Serum tumour markers<br>"] B --> C["Hydrocephalus present?<br>"] C --> D["No<br>"] & E["Yes<br>"] D --> F["LP for CSF tumour markers<br>"] E --> G["ETV and sampling of CSF<br>for tumour markers<br>"] F --> H["Evaluate tumour marker<br>levels<br>"] G --> H H --> I["Secreting<br>AFP >10 ng/ml<br>β-HCG >50 IU/l<br>"] & J["Non-secreting<br>AFP <10 ng/ml<br>β-HCG <50 IU/l<br>"] J --> K["Biopsy<br>"]
Radiology
CT
- Except mature teratomas, which often demonstrate fat density, CT cannot reliably differentiate between different types of germ cell tumours,
- Germinomas are more homogeneous in appearance than non-germinoma germ cell tumours
- General features of intracranial germ cell tumours include:
- Hyperdense compared to normal brain
- Vivid contrast enhancement
- Calcification: present in the majority of cases, usually representing engulfed normal pineal calcification, as well as sometimes tumour calcification
- Features of individual histologies are discussed separately.
Images
MRI
- Modality of choice for evaluation of pituitary region masses and pineal region masses.
- Synchronous pineal and pituitary lesion is pathogonomic
- Similar to CT, it is difficult to distinguish histologies based on MRI appearance (again, except for the identification of fat in mature teratomas).
- T1: isointense to grey matter
- T2: isointense to grey matter
- T1 C+
- Vivid contrast enhancement
- Germinomas tend to be homogeneous
- DWI:
- Restriction is common especially for germinomas due to high cellularity
- ADC values are higher than found in pineoblastoma
- SWI: haemorrhage is common in non-germinomatous germ cell tumours
Images
Biochemical
- Send both
- CSF
- Bloods
- Biomarkers
- ¹ Germinomas containing syncytiotrophoblastic giant cells may secrete β-HCG.
- ² Immature teratomas can rarely contain AFP or β-HCG secreting tissue; however, the differential diagnosis of mixed GCT containing yolk sac or choriocarcinoma components should also be considered.
Tumour | ㅤ | AFP | β-HCG | PLAP |
Germinomatous | Germinoma | – | +/–¹ | + |
Non-germinomatous | Mixed | +/– | +/– | +/– |
ㅤ | Teratoma | +/–² | +/–² | – |
ㅤ | Embryonal carcinoma | – | – | + |
ㅤ | Yolk sac tumour | + | – | +/– |
ㅤ | Choriocarcinoma | – | + | +/– |
- Results
- If biomarkers are negative then need biopsy
- If biomarkers + consistent radiological imaging → no biopsy required → treatment may be initiated
- AFP values > 25 ng/ml in serum and/or CSF are considered diagnostic
- HCG values > 50 IU/L in serum and/or CSF are considered diagnostic
Immunohistochemical panel for intracranial germ-cell tumour should include
- CD117/KIT (for germinoma)
- POU5F1 (OCT3/4) (germinoma)
- PLAP (germinoma)
- α-fetoprotein (yolk sac tumour)
- CD30 (embryonal carcinoma)
- HCG (choriocarcinoma or syncytiotrophoblast within germinoma)
Management of HCP
- ETV>EVD>VPS
- Benefits of ETV
- Effective: 80% remain shunt-free (Shono 2007)
- ETV allows biopsy at the same time
- ETV prevents VPS which has risk of iatrogenic tumour dissemination
- Chemo therapy, especially in the context of chemosensitive germinoma, results in rapid tumour shrinkage and the reopening of the cerebrospinal fluid pathways (within days) → Permanent shunt, with its inherent potential complications, can be avoided.
Management of tumour
Summary
Germ Cell Tumors (GCT) | Treatment Options |
Germinomas | Chemotherapy, radiation therapy, GKRS |
Non-germinomatous GCT | ㅤ |
– Teratomas (mature) | Surgical resection |
– Teratomas (immature) | Chemotherapy, radiation therapy, surgical resection, GKRS, hematopoietic stem cell rescue |
– Embryonal carcinomas | Chemotherapy, radiation therapy, surgical resection, GKRS, hematopoietic stem cell rescue |
– Choriocarcinomas | Chemotherapy, radiation therapy, surgical resection, GKRS, hematopoietic stem cell rescue |
– Yolk sac tumors | Chemotherapy, radiation therapy, surgical resection, GKRS, hematopoietic stem cell rescue |
- GKRS = Gamma knife radiosurgery
Detailed plan
- Current treatment recommendations for primary CNS GCT
Germ Cell Tumors (GCT) | Recommendations |
Germinomas | - 4 cycles of platinum based chemotherapy, usually including etoposide, ifosfamide, and either carboplatin or cisplatin |
ㅤ | - Followed by whole ventricular radiotherapy (20-24Gy) and boost radiation (12-16) to tumor bed |
ㅤ | - If CSF metastasis detected, then craniospinal irradiation also administered |
Non-germinomatous GCT | ㅤ |
– Teratomas (mature) | - Complete surgical resection |
– Teratomas (immature) / Embryonal carcinomas / Choriocarcinomas / Yolk sac tumors | - 4–6 cycles of neoadjuvant chemotherapy, usually including carboplatin/cisplatin, etoposide, and ifosfamide, but may include gemcitabine, taxanes, or vinblastine; however, immature teratomas do not respond well to cisplatin |
ㅤ | - More intensive chemotherapy regimens are recommended for worse prognosis NGGCT |
ㅤ | - Craniospinal irradiation (36Gy) and boost radiation (54Gy) to tumor bed or whole brain/ventricular radiation (24-40Gy) with boost radiation (15-30Gy) to tumor bed |
ㅤ | - Complete surgical resection when possible |
ㅤ | - Some suggest best protocol for poor prognosis NGGCT should include simultaneous radiation and chemotherapy followed by resection of remaining tumor |
Radiotherapy
- Radiosensitivity testing: Nakagawa 1992
- 20 Gy is given with a local irradiation field, if tumor regression is marked and germinoma is highly suspected, whole brain or whole CNS irradiation is performed subsequently; otherwise, surgical intervention is performed followed by systemic chemotherapy plus radiation therapy.
- May cause late adverse effects including neurological and cognitive impairment, secondary malignancy and endocrinopathy, especially in children.
- Efforts to reduce toxicity include
- Decreasing volume irradiated
- focal radiation is recommended for localised tumours
- Reducing the total dose
- Delivers 5-year survival rates comparable to older protocols
- Induction chemotherapy with focal irradiation that includes the ventricles in order to minimize the risk of dissemination
- The benefits of induction chemotherapy are being evaluated in ACNS 0232, a phase III RCT.
- Response-dependent decreases in radiation dose
- following induction chemotherapy a reduced radiotherapy dose is administered depending on radiological response
Non-germinomatous
General
- Low-risk (mature teratoma)
- Resection is curative
- Intermediate risk (mixed — predominantly germinoma/teratoma)
- Chemo + radio
- High risk (embryonal carcinoma, choriocarcinoma, yolk sac carcinoma)
- Induction chemotherapy, craniospinal irradiation +/- second-look surgery
Surgery
- Mature teratomas: resection is usually curative.
- Post chemotherapy residuum
- ‘Second-look’ surgery improves outcomes in non-germinomatous GCTs and recent trials encourage this approach
- Residuum can represent a mature teratoma (commonly), a different non- germinomatous tumour or necrosis/scarring.
- Normalization of tumour markers and increasing size of the residual lesion should prompt second-look surgery.
- Tumours unresponsive to adjuvant therapy
- These patients may benefit from surgery if they fail to respond to first and/ or second-line therapy.
Radiotherapy
- For non-germinomatous tumours radiotherapy results in poor 5-year PFS rates of less than 50%.
- For disseminated disease full Cranio-SpinaI irradiation is advised.
- For localized tumours, radiotherapy to the tumour and ventricles alone can be considered, however, 5-year PFS and OS rates were lower in the SIOP trial, which did not use CSI in localized tumours, versus the Children’s Oncology Group trial 5-year PFS 67–69% vs. 84.3%)
Chemotherapy
- Chemotherapy-only regimens produce dismal rates of survival (5-year PFS 50%, 3rd international CNS GCT trial).
- The MAKEI 89 trial used sandwich chemotherapy (chemotherapy- radiotherapy-chemotherapy), and survival rates were comparable to trials withholding second chemotherapy regimens if response was adequate
- Therefore, induction chemotherapy followed by radiotherapy +/– second-look surgery for residual, has become the standard of care for non-germinomatous tumours.
Metastatic germ cell tumours
- Defined by presence of two lesion in the CNS (brain and spine) on MRI and/or CSF cytology positivity
- Craniospinal radiotherapy +/- second-look surgery
Monitoring
- Serum tumour markers should be monitored during treatment and follow-up for intracranial germ-cell tumours, even if initially negative
- If there is signs of radiological or serum marker relapse, pt should be fully restaged and assessed
- Relapsed germinoma patients are salvageable with variable, but not yet standardised, treatment regimens.
- Relapsed non -germinomatous patients can be tx with high dose chemo + haematopoietic stem cell rescue + surgery + radiotherapy
Prognosis
General
- 5 year PFS rates
- Germinomas tumour: >90%
- Non-germinomatous tumours: 60–70%
- Local recurrence and cerebrospinal fluid-borne dissemination are the usual patterns of progression
- Abdominal contamination via VP shunts and haematogenous spread (principally to lung and bone) can occur.
Most disease relapse occurs intracranially and within 5 years of treatment
- Patients who relapse despite first-line treatment may benefit from high-dose salvage chemotherapy and/or autologous stem cell rescue.
- However patients with relapsed disease have a relatively poor prognosis, and median survival for
- Recurrent germinomas is 48 months
- Recurrent non-germinomatous tumours is 35 months
Depends heavily on histological subtype
- Low risk
- Mature teratoma are curable by surgical excision
- Pure germinomas are radio-sensitive
- Long term survival rates of >90% after craniospinal irradiation alone
- Intermediate risk: 10 yr OS rates: 70%
- Immature teratomas
- Mixed tumours dominated by teratoma or germinoma with only minor high-grade, non-germinomatous components
- Survival rates: 60-70% has been achieved with chemo- and radiotherapy
- High risk: 10 yr OS rates: 10%
- Yolk sac tumours
- Embryonal carcinomas
- Choriocarcinomas
- Mixed lesions in which the above are prominent.
Cognitive deficits
- Are present in a substantial proportion of patients
- Affect
- Working memory
- Processing speed
- Visual memory
- Neuropsychological sequelae are lower in patients with pineal GCTs compared to disseminated germ cell tumours.
- Patients treated with radiotherapy require long-term follow-up for late effects including cognitive impairment, endocrinopathy, and radiation- induced malignancy.
The prognostic significance of tumour markers is unclear.
- Some trials data have shown that elevated AFP and β-HCG do not influence survival
- In the SIOP trial
- Patients with isolated β-HCG levels of more than 50–200 IU/litre +/– non-germinomatous histology (except teratoma) were shown to have 5-year OS/PFS rates of 100%, similar to ‘pure’ germinomas.
- Only those with a β-HCG of more than 200 IU/litre had survival rates closer to those expected with non-germinomatous tumours,
- Suggesting that patients in the 50–200 group could simply be secreting germinomas
- In non-germinomatous tumours AFP greater than 1000 ng/ml has been demonstrated as marker of poor prognosis and these patients need more intensive treatment regimens
- Adult International Germ Cell Consensus Classification System (Frazier 2013)
Good risk | Intermediate risk | Poor risk |
Testis/retroperitoneal primary and no non-pulmonary visceral metastases | Testis/retroperitoneal primary and no non-pulmonary visceral metastases | Mediastinal primary or non-pulmonary visceral metastases |
Good markers—all of: | Intermediate markers—any of: | Poor markers—any of: |
AFP ≤1,000 ng/ml | AFP >1,000 ng/ml to ≤ 10,000 ng/ml | AFP >10,000 ng/ml |
Beta-hCG ≤5,000 IU/L | Beta-hCG >5,000 IU/L and ≤ 50,000 IU/L | Beta-hCG >50,000 IU/L |
LDH ≤1.59 × N | LDH >1.5 × N and ≤ 10 × N | LDH >10 × N |
Treatment outcomes
Study | Arm | Tumours | Metastases | Avg age, years (range) | Group size, n | Radiotherapy | Chemotherapy (induction) | Chemotherapy (post-XRT) | 5-year actuarial survival rates: PFS | 5-year actuarial survival rates: OS |
3rd international CNS GCT trial Non-randomized (Various) | Low-risk | Germinoma (β-HCG <2.2 IU/ml) | 0 | 15 (8–24) | 11 | None | 4 courses +/- additional based on response | None | 27.3%¹ | 88.9%¹ |
3rd international CNS GCT trial Non-randomized (Various) | intermediate and high-risk | NGGCT or germinoma with β-HCG >2.2 IU/litre | +/- | 10 (0.3–19) | 14 | None | Up to six courses of intensified carboplatin, cyclophosphamide, and etoposide | None | 50.0% | 58.3%¹ |
POG 9530 Non-randomized (USA) Response dependent irradiation doses | Low-risk | Germinoma (β-HCG <50 IU/ml) | 0 | - | 8 | Focal therapy CR: 30.6 Gy <CR: 50.4 Gy | 2 courses Cisplatin, Etoposide, Vincristine, Cyclophosphamide | None | 87.5% | 100% |
POG 9530 Non-randomized (USA) Response dependent irradiation doses | Low-risk | Germinoma (β-HCG <50 IU/ml) | 1 | 15.1 (9.5–17.7) | - | +CSI as follows CR: 30.6 Gy <CR: 36 Gy | 2 courses Cisplatin, Etoposide, Vincristine, Cyclophosphamide | None | 100% | 100% |
MAKEI 83/86/89 Non-randomized (German) No first-line chemotherapy | MAKEI 83/86 | Germinoma (β-HCG <100 ng/µl) | NR² | 13 (6-31) | 11 | CSI: 36 Gy Boost: 14 Gy | None | None | 100% | 100% |
MAKEI 83/86/89 Non-randomized (German) No first-line chemotherapy | MAKEI 89 | Germinoma (β-HCG <100 ng/µl) | - | - | 49 | CSI: 30 Gy Boost: 15 Gy | None | None | 88.8% | 92% |
MAKEI 89-NGGCT arm | N/A | NGGCT | +/- | 11 (2–24) | 27 | CSI: 30 Gy Boost: 20 Gy | 2 courses Cisplatin, Etoposide, Bleomycin | 2 courses Cisplatin, Etoposide, Vinblastine | 74% | 59% |
SIOP CNS GCT 96 Non-randomized (Various) Largest reported experience of intracranial GCTs | XRT only | Germinoma (β-HCG <50 IU/litre) | 0 | 13 (4–42) | 125 | CSI: 24 Gy Boost: 16 Gy | None | None | 97% | 95% |
SIOP CNS GCT 96 Non-randomized (Various) Largest reported experience of intracranial GCTs | XRT only | Germinoma (β-HCG <50 IU/litre) | 0 | - | 65 | 40 Gy focal | None | None | 88% | 96% |
SIOP CNS GCT 96 Non-randomized (Various) Largest reported experience of intracranial GCTs | Chemoradio | Germinoma (β-HCG <50 IU/litre) | 1 | - | 45 | CSI: 24 Gy Boost: 16 Gy | 2 courses Carboplatin, Etoposide, Ifosfamide | None | 100% | 98% |
SIOP CNS GCT 96 Non-randomized (Various) Largest reported experience of intracranial GCTs | No mets | NGGCT (unpublished data) | 0 | 12 (0–30) | 146 | Focal 54 Gy | 4 courses Cisplatin, Etoposide, Bleomycin | None | 69.0%⁴ | 78.0%⁴ |
SIOP CNS GCT 96 Non-randomized (Various) Largest reported experience of intracranial GCTs | Mets | NGGCT (unpublished data) | 1 | - | 43 | CSI: 30 Gy Boost: 24 Gy | 4 courses Cisplatin, Etoposide, Bleomycin | None | 67.0% | 70.0%⁴ |
Children's Oncology Group NGGCT trial Non-randomized (USA) Trial of NGGCTs | N/A | NGGCT or Germinoma with β-HCG > 50 IU/litre | +/- | 12 (3–23) | 102 | CSI: 36 Gy Boost: 18 Gy (primary) and >9 Gy (mets) | Up to six courses Carboplatin, Etoposide, Ifosfamide | If no response (+/- 2nd look surgery): thiotepa and etoposide | 84.3% | 93.0% |
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