Ovarian germ cell tumor differential diagnosis

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]Associate Editor(s)-in-Chief: Sahar Memar Montazerin, M.D.[2] Monalisa Dmello, M.B,B.S., M.D. [3]

Overview

Ovarian germ cell tumor must be differentiated from other diseases that cause ovarian mass, such as Stein-Leventhal syndrome, ovarian teratoma, tubal pregnancy, ovarian epithelial tumors, ovarian sex-cord stromal tumors, and tubo-ovarian abscess.

Differentiating Ovarian Germ Cell Tumor From Other Diseases

Ovarian germ cell tumor must be differentiated from other diseases that cause ovarian mass, such as:

• Stein-Leventhal syndrome
• Tubal pregnancy
• Ovarian epithelial tumors
• Ovarian sex-cord stromal tumors
• Tubo-ovarian abscess

Dysgerminoma and other ovarian germ cell tumors capable of producing B-hCG must be differentiated from other diseases that cause abdominal/pelvic mass and elevated levels of B-hCG.

Differentiating ovarian germ cell tumors from other diseases on the basis of age of onset, vaginal discharge, and constitutional symptoms

Diseases		Clinical manifestations						Para-clinical findings				Gold standard	Additional findings
		Age of onset	Symptoms			Physical examination
								Lab Findings	Imaging		Immunohistopathology
			pelvic/abdominal pain or pressure	vaginal bleeding/discharge	GI dysturbance	Fever	Tenderness		CT scan/US	MRI
Gynecologic
Ovarian	Embryonal carcinoma	Individuals of any age, especially young adults	+/–	+/–	_	_	_	Elevated concentration of alfa-fetoprotein (AFP)	Decreased echogenicity on the ultrasound imaging	The tumor is large, predominantly solid and unilateral with areas of necrosis and hemorrhage. There may be cystic areas that contains mucoid material.	AFP Cytokeratin (AE1/AE3) Placental-like alkaline phosphatase in 50% of the individuals. SALL4 (nuclear) in > 90% of the cases. GPC3	Biopsy	Tumor is usually a component of ovarian mixed germ cell tumors.
	Gonadoblastoma	Individuals of any age,but more common prior to 15 years of age	+/–	+/–	_	_	_	Elevated concentration of human chorionic gonadotropin (hCG), in case of coexisting dysgerminoma	Solid mass with focal or extensive calcifications with or without ascites Mass can be complex and have a cystic component Increased echogenicity on the ultrasound imaging	Solid mass with focal or extensive calcifications with or withous ascites Mass can be complex and have a cystic component	NA	Biopsy	Tumor is bilateral in 50% of cases Focal calcification can be present in 80% of individuals
	Follicular cysts	Women in reproductive age (15 -45 y/o)	+/–	–	–	–	+/–	High level of estrogen +/–	In US we may see a >3 cm simple cyst with no internal echo and with posterior acoustic enhancement	simple cyst with no internal echo or septa	NA	History/ imaging	It is associated with hyperestrogenism and endometrial hyperplasia
	Theca lutein cysts	Women in reproductive age (15 -45 y/o)	+/–	–	–	–	+/–	Depends on the underlying etiology	In US we may see bilaterally enlarged ovaries with multiple cysts	Multiple bilateral cysts	Theca interna cell Hyperplasia	History/ imaging	It is associated with hydatidiform moles, choriocarcinoma, diabetes mellitus and clomiphene intake (ovulation induction)
	Serous cystadenoma/carcinoma	>55 y/o	+/–	–	–	–	+/–	Elevated levels of serum cancer antigen-125	In US we may see simple or multiloculated cyst In serous cystadenocarcinoma we may see papillary projection inside the cyst In serous cystadenocarcinoma we may see ascites	In Serous cystadenoma we may see a simple cyst with beak sign, hypointense on T1 and hyperintense on T2 In serous cystadenocarcinoma we may see some Solid malignant components inside the cyst with intermediate signal on T1 and T2	Cyst wall consist of benign/malignant Fallopian epithelial layer Psammoma body In serous cystadenocarcinoma we may see papillary projection inside the cyst	Biopsy	Most common ovarian neoplasm
	Mucinous cystadenoma/carcinoma	>55 y/o	+/–	–	–	–	+/–	Elevated levels of serum cancer antigen-125	In US we may see large simple cyst with septation In mucinous cystadenocarcinoma we may see thickened internal septation with solid components inside the cyst	Stained glass appearance due to variable signal intensity on T1 and T2 The more mucin we have, there is more intensity on T1 and less intensity on T2	Cyst wall consist of columnar endocervical epithelium We may see gelatinous mucin inside the cyst	Biopsy	It may cause pseudomyxoma peritonei
	Endometrioma	Women in reproductive age (15 -45 y/o)	+	+	+/–	–	+	Iron deficiency anemia Elevated levels of serum cancer antigen-125 Increased levels of interleukin 1, chemoattractant protein-1, and interferon gamma	Complex mass on US Increased Doppler flow because of increased vascularture It may present with catamenial pneumothorax, hemothorax, and lung nodules in CT scan.	hyperintensity on T1-weighted images and a hypointensity on T2-weighted images Powder burn hemorrhages	Chocolate cyst	Laparoscopy	It may cause infertility
	Teratoma	10-30 y/o	+/–	–	–	–	+/–	High level of HCG and LDH	In US we may see cystic adnexal mass with mural components and echogenic lesion due to calcification The iceberg sign Dot-dash pattern	We may see evidence of fat components	All three germ layers cell	Biopsy	It may cause ovarian torsion May content thyroid tissue and cause hyperthyroidism In plane radiography we may see calcification due to the presence of tooth in the tumor
	Dysgerminoma	in the second to third decade of life	+	+/–	–	–	+/–	High level of HCG and LDH Hypercalcemia	Multilobulated solid masses	We may see ovarian mass with septation which are hyperintense on T1 and hypo or isointense on T2 imaging	Sheets fried egg appearance cells	Biopsy	Same as male seminoma
	Yolk sac tumor	Young children Male infants	+	–	–	–	+	High levels of AFP	In US we may see a combination of echogenic and hypoechoic components	Ovarian mass with hemorrhagic areas	Yellow appearance Hemorrhagic Schiller-Duval bodies (glomeruli like structures)	Biopsy	The other name is ovarian endodermal sinus tumor
	Fibroma	>50 y/o	Pulling sensation in the groin	–	–	–	+/–	High levels of CA-125	In CT scan we may see a unilateral mass with poor contrast enhancement	Low signal intensity on T1 and T2 We may see scattered hyperintense areas due to edema or cystic degeneration	Spindle-shaped fibroblast	Biopsy	It may cause Meigs syndrome (ovarian fibroma, ascites, and hydrothorax) It may cause ovarian torsion It may cause pleural effusion
	Thecoma	>50 y/o	+/–	Postmenopausal bleeding	–	–	–	High level of estrogen	In US we may see non-specific ovarian mass We may see evidence of endometrial hyperplasia due to increased level of estrogen	Hyperintense on T2 T1 intensity depends on the amount of fibrous tissue (fibrous tissue lead to hypointensity)	Lipid-laden stromal cells with pale, vaculolated cytoplasm	Biopsy	We may see endometrial cancer as e result of hyper-estrogenism We may see ovarian fibrothecoma (mixture of fibroma and thecoma)
	Granulosa cell tumor	50-60 y/o	+	Postmenopausal bleeding	+/–	–	–	High level of estrogen and progesteron We may see inhibin, calretinin, and Ki-67 on the surface of granulosa tumor cells	In US we may see solid, cystic, or multiloculated solid and cystic mass	We may see solid, cystic, or multiloculated solid and cystic mass	Call-Exner bodies	Biopsy	In postmenopausal women may cause breast tenderness
	Sertoli-leydig cell tumor	15 to 35 y/o	+/–	–	–	–	–	Elevated serum testosterone level Elevated alpha-fetoprotein	In US we may see unilateral Well-defined hypoechoic lesion	Low T2 signal intensity areas of high signal intensity	Lydig cells (Polygonal pink cells with eosinophilic cytoplasm Sertoli cells (clear vacuolated cytoplasm)	Biopsy	It may cause virilization symptoms and amenorrhea
	Brenner tumor	>55 y/o	+/–	–	–	–	–	–	In US we may see hypoechoic solid mass and calcification	Hypointense on T2 because of fibrous content	Yellow/pale appearance Transitional cell tumor (resembles bladder) Coffee bean nuclei on H&E	Biopsy	Most of the times it's an accidental finding
Krukenberg tumor	>55 y/o	+/–	–	+/– Based on underlying malignancy	–	–	In case of metastatic GI cancers we may see iron deficiency anemia	Mostly bilateral, complex ovarian lesion In CT scan we may see evidence of concurrent malignancy in other organs	Mostly bilateral, complex ovarian lesion with solid components Internal hyperintensity on T1 and T2 weighted MR images because of mucin Evidence of concurrent malignancy in other organs	Mucin-secreting signet cell	Imaging/ biopsy	The most common primary tumor is in colon, stomach, breast, lung, and contralateral ovary Based on underlying malignancy it may cause pleural effusion
Tubal	tubo-ovarian abscess	Young women (15-30 y/o	+	+	–	+	+	High levels of inflammatory markers Leukocytosis	In US we may see multilocular complex lesion mostly bilateral with debry inside	We may see a pelvic mass filled with fluid with thick walls hypointense in T1 and heterogeneous in T2	In abscess aspiration we may see anaerobic organisms	History/ imaging	The most common risk factors are previous PID, diabetes mellitus, intrauterine device and history of uterine surgery
	Ectopic pregnancy	Women in reproductive age (15 -45 y/o)	+	+	+/–	–	+	High level of BhCG Progesterone level ≤5 ng/ml	In US we may see empty uterine cavity, tubal ring sign, ring of fire sign (Doppler), extra-uterine fetal heart rate	NA	NA	History/ imaging	Any women in reproductive age presenting with abdominal pain or amenorrhea should be screened for ectopic pregnancy
	Hydrosalpinx	NA	+	–	–	–	+/–	–	In US we may see tubal longitudinal folds thickening (cogwheel appearance) In CT scan we may see tubular adnexal lesion with fluid attenuation	Dilated Fallopian tube with fluid signal intensity	NA	Imaging	It is associated with endometriosis (haematosalpinx), ovulation induction, pelvic inflammatory disease, post-hysterectomy, tubal ligation, and tubal malignancy It may cause infertility
	Salpingitis	Women of reproductive age	+	+	–	+	+	Leukocytosis	In US we may see , edematous and thickened endosalpingeal folds	NA	NA	History/ physical exam	It may cause infertility
	Fallopian tube carcinoma	>60 y/o	+	+	+	–	+/–	High levels of CA125	US findings are non specific (complex mass on Fallopian tube We may see papillary projections	Low signal on T1 In case of hemorrhage inside the tumor we may see high signal intensity on T1 Low or of intermediate signal on T2 In case of serous fluid inside the tumor we may see high signal intensity on T2	Based on the tumor type we may have different biopsy finding	Biopsy	We may see Latzko triad (abdominal pain, vaginal discgarge, pelvic mass) It may cause pleural effusion
Uterine	Leiomyoma	Women of reproductive age	+	+	–	–	+/–	In chronic cases, we may see mild anemia	In US we may see hypoechoic mass with calcification and cystic areas of necrosis or degeneration may	Low to intermediate signal intensity on T1 and T2 In case of necrosis inside the mass, there might be some high signal lesions on T2	Smooth muscle	Imaging	It may cause infertility
	Choriocarcinoma	Women in reproductive age (15 -45 y/o)	+	+	+/–	–	+	High level of B-hCG	In US we may see heterogeneous mass infiltrating myometrium Enlarged uterus Necrosis + Hemorrhage + In CT scan we may see evidence of metastasis to brain, lung and other organs	We may see an infiltrative uterine mass and thickening of uterine wall	Trophoblastic tissue origin columns and sheets of trophoblastic tissue invading uterine muscle and blood vessels	Biopsy	It is associated with bilateral theca lutein cysts Cannonball metastases to the lungs May cause hemoptysis We may see passing of grapes like tissue from the vagina
	Leiomyosarcoma	>55 y/o	+	+	–	–	+/–	In some cases we may see elevated levels of CA-125 lactate dehydrogenase	Heterogeneous mass with central low attenuation (necrosis) and calcification.	Increased uterine size Irregular central zones of low signal intensity (tumor necrosis)	We may see atypical cells, high mitotic rate, geographic areas of coagulative necrosis separated from viable neoplasm	Biopsy	In case of rapid uterine growth in post menopausal women we may suspect uterine sarcoma
	Pregnancy	Women in reproductive age (15 -45 y/o)	+/−	+/−	+/−	–	–	High level of BhCG	In US we may see gestational sac, yolk sac, double bleb sign and fetal pore In CT scan we may see cystic structure filled with fluid, curvilinear enhancing structure (placenta) and fetal pore	Cystic structure filled with fluid Curvilinear enhancing structure (placenta) Fetal pore	NA	History/ laboratory findings	We do not perform CT scan and MRI in pregnancy but We may unintentionally image the pregnancy with CT scan and MRI.
Non-gynecologic
GIT	Appendiceal abscess	NA	+	–	+	+/–	+	Leukocytosis	Fluid collection in the appendicular region appendicolith may be visualized.	Fluid collection in the appendicular region appendicolith may be visualized.	NA	Imaging/ history	The most common complication of acute appendicitis It may cause pleural effusion
	Appendiceal neoplasm	60-70 y/o for adenocarcinoma, 30-50 y/o for carcinoid tumors	+	–	+	–	+/–	In adenocarcinoma type we may have high levels of CEA and CA 19-9 In carcinoid type we may see high levels of chromogranin A, 5-HIAA and Ki67	In CT scan we may see: Soft tissue thickening and Cystic lesion with Internal septation Wall irregularity Calcification Peri-appendiceal fat stranding	Soft tissue mass in the appendix We may see invasion to other structures	Gray/yellowi color Cystic structures with angiolymphatic invasion	Biopsy	It is associated with: MEN1 syndrome Ulcerative colitis Neurofibromatosis type 1 HNPCC Smoking It may cause pleural effusion
	Diverticular abscess	>50 y/o	+	–	+	+/–	+	Leukocytosis	Ill-defined lesion with air and fluid inside Adjacent bowel loop wall thickening Smudged mesenteric fat	We may see a lesion with air and fluid inside	NA	Imaging/ history	Diverticular abscess happens in almost 30-40% of patients with diverticulitis It may cause pleural effusion
	Colorectal cancer	>50 y/o	+	–	+	–	+/–	Anemia Positive Fecal occult blood test High levels of CEA and CA 19-9	In CT scan we may see luminal narrowing, intestinal wall thickening,intussusception, bowel obstruction, hepatic metastases, intestinal perforation,enlarged lymph nodes	We may see tumor mass and the extension of tumor to other structures We may see metastasis to the liver, lung and brain	Based on the sub-type we may have different histopathological feature (for more information click here)	Biopsy	It is associated with smoking, positive family history, processed meat, low fiber diet, lynch Syndrome and familial adenomatous polyposis They have apple core lesion on barium enema xray
Renal Bladder	Pelvic kidney	NA	−/+ In case of sever hydronephrosis or renal stone we may have pelvic pain	–	−	−	−	−	In sonography we may see normal appearing kidney in pelvic position We may see renal calculi	We may see normal kidney structure Renal calculi	NA	Imaging	It may cause hypertension It may cause tract infection (UTI), obstruction, and renal calculi. It may be associated with RCC
	Bladder cancer	≥65 y/o	+	–	–	–	–	Low red blood cell count Elevated alkaline phosphatase Positive tumor markers such as BTA, NMP, and CEA	In CT scan we may see masses protruding into the bladder lumen or asymmetric thickening of the bladder calcifications Nodal metastases	isointense compared to muscle in T1 slightly hyperintense compared to muscle in T2	Based on the sub-type we may have different histopathological feature (for more information click here)	Biopsy	It may presents with hematuria
Others	Retroperitoneal sarcoma	40-50 y/o	+	–	+	−	−	Mild leukocytosis. It may cause hypoglycemia because of production of insulinlike substances	We may see irregular solid, semisolid, liquefactive areas and patchy necrosis on CT scan	We may see retroperitoneal involvement and degree of tumor extension We may see liver and lung metastasis	There are two types: liposarcoma and leiomyosarcoma In liposarcomas we may see background of adipocytes with scattered lipoblasts, and inflammatory cell infiltrate In leiomyosarcoma we may see smooth muscle cells	Biopsy	May cause lower extremity edema, Serous ascites we should perform chest CT scan to rule out pulmonary metastases

ABBREVIATIONS

BTA=Bladder tumor associated antigen, NMP= Nuclear matrix proteins, CEA= Carcinoembryonic antigen, US= Ultrasound, HCG= Human chorionic gonadotropin, LDH= Lactate dehydrogenase, AFP= Alpha fitoprotein, CA125= Cancer antigen 125, H&E= Hematoxylin and eosin, MRI= Magnetic resonance imaging, GI= Gastrointestinal tract, PID= Pelvic inflammatory disease, CA19-9= Carbohydrate antigen 19-9, 5HIAA= 5-hydroxyindoleacetic acid, MEN syndrome= Multiple endocrine neoplasia syndrome, HNPCC= Hereditary nonpolyposis colorectal cancer, UTI= Urinary tract infection, RCC= Renal cell carcinoma