1. Juvenile Granulosa Cell Tumor and Small Cell Carcinoma of hypercalcemic Type
Ming-Chieh Lin 林明杰

2. Juvenile Granulosa Cell Tumor
Epidemiology
5% of GCT
Children and young adult: < 30 y/o
Average 15 years old
Macroscopy
< 5% bilateral
2% extraovarian spread
Size:
Average: 12 cm
Cut surface:
Similar to those encountered in adult type GCT

3. JCGT Yellow tan solid tumor with cysts and hemorrhage and necrosis
Entirely yellow solid tumor
Predominantly cystic tumor

4. Juvenile Granulosa Cell Tumor
Microscopy
Growth pattern: nodular or diffuse cellular growth punctuated by macrofollicles of varying sizes and shapes
The follicular lumens contain basophilic (or eosinophilic) fluid
Fibrothecomatous stroma with variable luteinized cells
Granulosa cells: abundant eosinophilic and/or clear cytoplsam without grooved nuclei
Striking bizarre nuclear atypia: 10-15%
Mitotic activity: abundant
Immunohistochemistry
Similar to adult type GCT: α-inhibin (+)
FOXL2: rare

5. Nodular pattern
Granulosa cells: abundant eosinophilic
cytoplasm with frequent mitoses,
lacking grooved nuclei
Diffuse pattern with
macrofollicles containing
basophilic fluid

6. Marked nuclear atypia in JGCT

7. Juvenile Granulosa Cell Tumor
Histogenesis
? Granulosa cells of ovarian follicles
Frequent absence of FOXL2 immunostain
Distinctive from adult type GCT
Genetic profile
Trisomy 12 in most cases
FOXL2 gene mutation
absent

8. Juvenile Granulosa Cell Tumor
Genetic susceptibility
JGCT may present as a component of some non-hereditary congenital syndromes
Ollier disease (enchondromatosis)
Maffucci syndrome (enchrondromatosis and multiple subcutaneous hemangiomatosis)
Goldenhar (craniofacial and skeletal abnormalities) or Potter syndrome: bilateral JGCT in infants

9. Juvenile Granulosa Cell Tumor
Prognosis
Good prognosis
5% behave aggressively
High stage tumors:
Often fatal
Recurrence almost always occur within 3 yrs
Predictive factors
Stage is the most important prognostic factor
Tumor rupture
Positive peritoneal cytology
Extra-ovarian tumor spread

10. Juvenile Granulosa Cell Tumor
Differential diagnosis
Small cell carcinoma, hypercalcemic type
Hyeprcalcemia
20% dissemination beyond the ovary
10% mucinous glands
α-inhibin (-)
Epithelial markers (±) in both tumors

11. Small Cell Carcinoma, Hypercalcemic type
Definition
An undifferentiated carcinoma, ususally associated with paraendocrine hypercalcemia and composed primarily of small cells
Clinical features
The most common form of undifferentiated carcinoma of ovary in females < 40 yrs
Young (2 to 46 y/o, most commonly y/o; average:24)
2/3: hypercalcemia

12. Small Cell Carcinoma, Hypercalcemic type
Macroscopy
Large, solid and fleshy, with hemorrhage, necrosis, and cystic changes
Resembling lymphoma or dysgerminoma
Unilateral

13. Small Cell Carcinoma, Hypercalcemic type
Microscopy
Diffusely distributed, closely packed round tumor cells with high N/C ratio and a high mitotic rate
Occasional small island, trabeculae or cord arrangement
Follicle-like spaces containing eosinophilic fluid
Mucinous glands:
10-15%; benign or malignant
Large cell variants:
~50%
Large cells with abundant eosinophilic or clear cytoplasm and nuclei with prominent nucleoli

14. Juvenile GCT
Small cell carcinoma,
hypercalcemic
Follicle-like spaces with eosinophilic fluid

15. Mucinous glands
Closely packed round tumor cells
with high N/C ratio and a
high mitotic rate

16. Sertoli-Leydig cell tumor
with mucinous glands
Small cell carcinoma, hypercalcemic
type with mucinous glands

17. Small Cell Carcinoma, Hypercalcemic type
Immunoprifile
Variable staining for vimentin, CK, EMA
α-inhibin (-), Synaptophysin (-), Chromogranin (-)
Histogenesis
Not been definitively established
? A variant of a surface epithelial tumor
In one study, by comparative genomic hybridization and EM:
A distinct entity, not related to either germ cell tumor or epithelial tumor
Sex cord-stromal cell tumor variant :
Young age
Diffuse small cells, with follicles

18. Small Cell Carcinoma, Hypercalcemic type
Hypercalcemia
No parathyroid hormone (PTH) within tumor cells or serum
PTH-related peptide (PTHRP)
In the serum and tumor cells in some cases
Binding to a receptor common for PTH and PTHRP
1,25-dihydroxyvitamin D (1,25-DHD) in one case
High serum level and intestinal calcium absorption
Tumor removal:
Serum level of calcium, PTHRP, 1,25-DHD: normal
Intestinal contribution to the maintenance of hyhpercalcemia

19. Small Cell Carcinoma, Hypercalcemic type
Genetic susceptibility
Familial in several instances:
Often bilateral
Prognosis
Poor:
Extra-ovarian involvement in ~50% patients at the time of diagnosis

20. Small Cell Carcinoma, Hypercalcemic type
Prognosis
In one 150 cases study (1994, RH Young & RE Scully)
1/3 of p’t with stage IA:
Disease-free: 1-13 yrs, average, 5.7 yrs
The remainder had progressive disease at relatively short postoperative intervals
Most higher stage p’ts: died of disease within 2 yrs
Rare high-stage p’t, receiving intensive C/T and/or R/T, were alive up to 6.5 yrs
Features, in stage IA, associated with favorable outcome
> 30 y/o
Normal preoperative calcium level
Tumor < 10 cm
Absence of large cells
Bilateral oophorectomy and post-op R/T

21. Small Cell Carcinoma, Hypercalcemic type
Differential diagnosis
Granulosa cell tumor, adult or juvenile type
Sertoli-Leydig cell tumor of intermediate and poor differentiation
Endometrioid stromal sarcoma
Small cell carcinoma, pulmonary type
Malignant lymphoma
Small blue round cell tumors
Primitive neuroectodermal tumor
Malignant melanoma
Rhabdomyosarcoma
Desmoplastic small round cell tumor

23. NTUH S
A 39 y/o female, left ovarian tumor (12 x 10 x 8 cm) with predominantly solid and occasionally cystic change

24. 40X
Diffuse pattern with edematous
stroma
20X

25. 400X

26. 100X
Follicle-like spaces with
eosinophilic fluid
100X

27. 40X
Nest of large cells
400X

28. 40X
Mucinous glands
400X

29. NTUH S
S (9/2005)
S (5/2007), recurrent, 病危出院

30. NTUH S
37 y/o female, left ovarian tumor, 10 x 7 x 5 cm in size, solid with focal cystic change

31. Large cells
400X

32. NTUH S06-22726 Diagnosis Small cell carcinoma, hypercalcemic type
S (3/2007), recurrent, with hypercalcemia
S (6/2007), recurrent, with hypercalcemia
2/2008: expired