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

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

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

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

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

Marked nuclear atypia in JGCT

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

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

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

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

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 10-30 y/o; average:24) 2/3: hypercalcemia

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

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

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

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

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

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

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

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

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

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

NTUH S05-25251 A 39 y/o female, left ovarian tumor (12 x 10 x 8 cm) with predominantly solid and occasionally cystic change

40X Diffuse pattern with edematous stroma 20X

400X

100X Follicle-like spaces with eosinophilic fluid 100X

40X Nest of large cells 400X

40X Mucinous glands 400X

NTUH S05-25251 S05-25251 (9/2005) S07-15761 (5/2007), recurrent, 病危出院

NTUH S06-22726 37 y/o female, left ovarian tumor, 10 x 7 x 5 cm in size, solid with focal cystic change

Large cells 400X

NTUH S06-22726 Diagnosis Small cell carcinoma, hypercalcemic type S07-05724 (3/2007), recurrent, with hypercalcemia S07-18378 (6/2007), recurrent, with hypercalcemia 2/2008: expired