Case Study 55

1. Case Study 55 Kenneth Clark, MD

2. Question 1 • This is a 27-year-old man with a history of pineal / dorsal midbrain region teratoma at age 16, status-post multiple debulking resections, chemotherapy, and gamma knife radiotherapy in 2001 & 2006. He presents to the emergency room following a grand mal seizure. He immediately underwent an MRI scan of the head. • How would you describe the neuroradiologic findings?

3. Axial T1 Axial T1 + Contrast Axial T2 FLAIR Sagittal T1 Coronal T1 + Contrast

4. Answer • A large expansile multicystic mass centered within the pineal region causing mass effect and distortion of the adjacent brain stem and extending superiorly to the level of the splenium of the corpus callosum. The lesion shows complex heterogeneous enhancement (T1 + Contrast) and T2 FLAIR activity in contiguous white matter regions. Overall, the mass showed mild interval enlargement since the most recent surveillance scan 9 months prior.

5. Question 2 • Name at least 5 intracranial lesions that have cystic changes

6. Answer • Juvenile Pilocytic Astrocytoma (JPA) • Ganglioglioma • Hemangioblastoma • Pineal Cyst • Dermoid/Epidermoid Cyst • Rathke Cleft Cyst • Metastatic Lesions • Colloid Cyst • Teratoma

7. Question 3 • How common are CNS germ cell tumors and what are the different histologic subtypes?

8. Answer • Of all primary CNS neoplasms, CNS germ cell tumors account for approximately 0.3-0.6% in the United States and as high as 3% in the east Asia. They account for approximately 3-5% of all intracranial tumors seen in patients younger than 20 years of age. • Types of germ cell tumors • Pure germinoma ~ 65% • Non-germinomatous germ cell tumors (NGGCT) ~ 35% • Teratoma (mature or immature) ~ 15% • Mixed ~ 20% • Choriocarcinoma, embryonal carcinoma, Yolk sac tumor

9. Question 4 • Where do CNS germ cell tumors usually occur?

10. Answer • The gross majority of CNS germ cell tumors occur along the midline, most often in the pineal and suprasellar regions (>90%), although cases have been reported in virtually all areas of the brain.

11. Question 5 • What is the demographic profile of germ cell tumors (age and sex distribution)?

12. Answer • They typically affect children and young adults (first and second decades of life) with a the peak incidence is from 10-19 years of age. The exception is pure germinoma, with a peak incidence in the 5th decade of life. There is a clear male predominance, ranging from 75-90% depending of the histologic subtype.

13. Question 6 • In what way are teratomas histopathologically unique, and what are the three general types of teratomas?

14. Answer • Teratomas differentiate along all three embryonic germ cell layers – endodermal, mesodermal and ectodermal. Likewise, they recapitulate a combination of corresponding tissues/structures from these three layers. • Types: • Mature (composed of fully differentiated elements) • Immature (incompletely differentiated “fetal” elements) • Teratoma with Malignant Transformation

15. Question 7 • A portion of the lesion was resected and submitted for pathological examination. Describe the findings.Is there anything particularly unusual or concerning? • Click here to view the slide

16. Answer • The majority of the sample is comprised of dense fibrous tissue admixed with regions of necrosis. One focus shows well-differentiated glandular epithelium with cribriforming marked architectural tortuosity. The cells show moderate nuclear pleomorphism with hyperchromasia, clumped chromatin and contour irregularities. Many of the atypical cells show cytoplasmic vacuoles and appear to be producing mucinous material. • This kind of atypia is unusual for teratoma with mature elements and is concerning for adenocarcinoma.

17. Question 8 • Which stains would you order to help better characterize the lesion?

18. Answer • Cytokeratins (CK7, CK20, Pankeratin) • Mucicarmine • Germ cell markers (AFP, Oct-4, Glypican, SALL4) • Ki67 (proliferation marker) • Click to view CK7, Mucicarmine, Ki67

19. Question 9 • Based on the results of the stains (see below) and H&E slides, what is the most compatible diagnosis? • CK7 – strong diffuse staining of tumor cells • CK20 – negative • Mucicarmine – highlights mucin in tumor cells and glandular lumens • Ki67 – strong staining of 40-50% tumor cells overall, focally up to 80% • AFP – negative • Glypican3 – negative • Oct4 – negative • SALL4 - negative

20. Answer • Mucin-producing adenocarcinoma arising in a previously irradiated teratoma (Carcinoma Ex Teratoma)

21. Question 10 • How often does malignant transformation occur in teratomas?

22. Answer • Malignant transformation in teratomas is exceedingly rare. These typically are case reports.

23. Question 11 • Would evaluation of serum markers (AFP, HCG) have been useful in detecting this lesion earlier?

24. Answer • No. While many germ cell tumors are associated with elevated tumor marker secretion, teratomas (and germinomas) are not. This patient had normal serum tumor markers at the time or resection.

25. References • Louis D, Ohgaki H, Wiestler O, Cavanee W. WHO Classification of Tumours of the Central Nervous System. IARC: Lyon 2007. • Echevarria M, Fangusaro J, Goldman S. Pediatric Central Nervous System Germ Cell Tumors: A Review (2008). The Oncologist. 13:690-699. • Fujimaki T. Central Nervous System Germ Cell Tumors: Classification, Clinical Features, and Treatment With a Historical Overview (2009). Journal of Child Neurology. 24(11):1439-1445. • Freilich R, Thompson S, Walker R, Rosenblum M. Adenocarcinomatous Transformation of Intracranial Germ Cell Tumors (1995). Am J Surg Path. 19:537-544.