Sexcord/ stromal ovarian tumors

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: ; Maneesha Nandimandalam, M.B.B.S.[2]

Ovarian sex cord-stromal tumors are a diverse group of both benign and malignant neoplasms that develop from the dividing cell population which would normally give rise to cells that surrounds the oocytes, including the cells that produce ovarian hormones (the nongerm cell and nonepithelial components of the gonads).The yearly adjusted incidence rate is approximately 2 per 1,000,000 women for sexcord-stromal ovarian tumors(SCSTs). The mortality rate has gradually been declining from1976 (10.0 per 100,000) and 2015 (6.7 per 100,000) by 33%. The age at presentation varies depending on the subtypes of sexcord-stromal ovarian tumors. Sexcord-stromal ovarian tumors(SCSTs) have more predilection in women of Caucasian background. Rates are highest among Whites, intermediate for Hispanics, and lowest among Blacks, and Asian people. Sexcord/ stromal ovarian tumors may be classified according to WHO into 3 subtypes: Pure stromal tumors, pure sexcord tumors, mixed stromal and sexcord tumors. Histological classification of sexcord-stromal ovarian tumors includes granulosa stromal cell tumors, sertoli leydig cell tumors, gynandroblastoma, and unclassified. The exact pathogenesis of sexcord/ stromal ovarian tumors is not fully understood. Mutations mainly involving FOXL2, DICER1, STK11 are involved. They are associated with ollier disease and maffucci syndrome.The microscopic pathology varies with the individual subtype of sexcord stromal ovarian tumors.Common risk factors in the development of sexcord/ stromal ovarian tumors include preterm birth, high gonadotrophin levels, increasing age at first pregnancy, obese and non-white women.The symtoms of sexcord/ stromal ovarian tumors include Adnexal mass, Abdominal & pelvic symptoms, Bloating, Urinary urgency or frequency, Dysphagia(difficulty)eating) or feeling full quickly, Pelvic or abdominal pain. Common complications of sexcord/ stromal ovarian tumors include malignant pleural effusion,bowel obstruction,ascites. The prognosis varies with the subtypes of tumor. Most sexcord-stromal ovarian tumors present at a low tumor stage and also prognosis in these patients is excellent. CT and MRI are very helpful in the diagnosis of these tumors. Surgery and chemotherapy are the mainstay of treatment for these tumors.

There is limited information about the historical perspective of sexcord/ stromal ovarian tumors

Sexcord/ stromal ovarian tumors may be classified according to WHO into 3 subtypes: Pure stromal tumors, pure sexcord tumors, mixed stromal and sexcord tumors. Histological classification of sexcord-stromal ovarian tumors includes granulosa stromal cell tumors, sertoli leydig cell tumors, gynandroblastoma, and unclassified.

The exact pathogenesis of sexcord/ stromal ovarian tumors is not fully understood. Mutations mainly involving FOXL2, DICER1, STK11 are involved. They are associated with ollier disease and maffucci syndrome.The microscopic pathology varies with the individual subtype of sexcord stromal ovarian tumors.

The cause of sexcord/ stromal ovarian tumors has not been identified.Mutations mainly involving FOXL2, DICER1, STK11 are involved.

On the basis of age of onset, vaginal discharge, and constitutional symptoms, ovarian cancer must be differentiated from tubo-ovarian abscess, ectopic pregnancy, hydrosalpinx, salpingitis, fallopian tube carcinoma, uterine leiomyoma, choriocarcinoma, leiomyosarcoma, pregnancy, appendiceal abscess, appendiceal neoplasm, diverticular abscess, colorectal cancer, pelvic kidney, advanced bladder cancer, and retroperitoneal sarcoma.

The yearly adjusted incidence rate is approximately 2 per 1,000,000 women for sexcord-stromal ovarian tumors(SCSTs). The mortality rate has gradually been declining from1976 (10.0 per 100,000) and 2015 (6.7 per 100,000) by 33%. The age at presentation varies depending on the subtypes of sexcord-stromal ovarian tumors. Sexcord-stromal ovarian tumors(SCSTs) have more predilection in women of Caucasian background. Rates are highest among Whites, intermediate for Hispanics, and lowest among Blacks, and Asian people. Intrestingly there has been increases in incidence and mortality rates in less developed countries with recent economic growth and lifestyle changes.

Common risk factors in the development of sexcord/ stromal ovarian tumors include preterm birth, high gonadotrophin levels, increasing age at first pregnancy, obese and non-white women

There is insufficient evidence to recommend routine screening for sexcord/ stromal ovarian tumors. According to the US Preventive Services Task Force(USPSTF) , screening for sexcord/ stromal ovarian tumors is not recommended in asymptomatic women

The symtoms of sexcord/ stromal ovarian tumors include Adnexal mass, Abdominal & pelvic symptoms, Bloating, Urinary urgency or frequency, [[Dysphagia](difficulty)eating) or feeling full quickly, Pelvic or abdominal pain. Common complications of sexcord/ stromal ovarian tumors include malignant pleural effusion,bowel obstruction,ascites. The prognosis varies with the subtypes of tumor. Most sexcord-stromal ovarian tumors present at a low tumor stage and also prognosis in these patients is excellent.

Biopsy is the gold standard test for the diagnosis of sexcord/ stromal ovarian tumors. There is no single diagnostic study of choice for the diagnosis of sexcord/ stromal ovarian tumors, but these can be diagnosed based on CT and MRI findings

The most common symptoms of sexcord/ stromal ovarian tumors include adnexal mass, bloating, urinary urgency or frequency, dysphagia(difficulty eating) or feeling full quickly, pelvic or abdominal pain. Less common symptoms of sexcord/ stromal ovarian tumors include lymphadenopathy, postmenopausal bleeding, typical features of bowel obstruction like nausea, vomiting, and distention. Specific symptoms pertinent to sexcord/ stromal ovarian tumors include hirsutism(excessive hairgrowth), virilization, menstrual changes like abnormal uterine bleeding, precocious puberty in children.

Patients with sexcord/ stromal ovarian tumors usually appear normal except few abdominal or pelvic and genitourinary findings on examination. Abdominal findings include Abdominal distension, increased abdominal girth, abdominal tenderness in the right/left lower abdominal quadrant, a palpable abdominal mass in the right/left lower abdominal quadrant, guarding, ascites, hemoperitoneum.

Laboratory findings consistent with the diagnosis of sexcord/ stromal ovarian tumors include identifying the presence or absence of tumor markers like AMH: anti-Müllerian hormone; AFP: alpha-fetoprotein; E2: estradiol; hCG: human chorionic gonadotropin; LDH: lactate dehydrogenase; testost: testosterone; andro: androstenedione; DHEA: dehydroepiandrostenedione;

There are no ECG findings associated with the diagnosis of sexcord-stromal ovarian tumors.

There are no x-ray findings associated with sexcord/ stromal ovarian tumors.

There are no echocardiography findings associated with sexcord/ stromal ovarian tumors. Ultrasound may be helpful in the diagnosis of sexcord/ stromal ovarian tumors. Findings on an ultrasound suggestive of sexcord/ stromal ovarian tumors include adnexal hypoechoic masses with clear border and acoustic attenuation as well as minimal doppler flow signals.

Pelvic ct scan may be helpful in the diagnosis of sexcord/ stromal ovarian tumors. Findings on CT scan suggestive of sexcord/ stromal ovarian tumors include multicystic masses with solid components and either irregularly thickened or thin septations for both adult and juvenile granulosa cell tumors, Fibromas on delayed contrast-enhanced computed tomography usually shows a solid, well-defined, homogeneous ovarian mass which is isodense to the uterus with very sparse contrast uptake. Sclerosing stromal tumor will show peripheral contrast uptake, reflecting prominent vasculature in the cellular areas, with centripetal progression on late images. Leydig tumors tend to be small and hypoattenuating.

MRI may be helpful in the diagnosis of sexcord/ stromal ovarian tumors. Findings on MRI suggestive of sexcord/ stromal ovarian tumors depends on the tumor subtypes. Granulosa cell tumors show heterogeneous signal intensity on both T1WI and T2WI and high signal intensity on DWI images. Fibroma, Fibrothecoma, and Thecoma appear as hypointense masses on T1-weighted MRI with very low signal intensity on T2-weighted imaging. Sclerosing stromal tumor of ovary show hyperintense cystic components or a heterogeneous solid mass of intermediate to high signal intensity on T2-weighted MRI.

PET-CT may be helpful in the diagnosis of sexcord/ stromal ovarian tumors. On fluorodeoxyglucose–positron emission tomography/computed tomography malignant ovarian tumors generally have intense uptake, whereas tumors with a small solid content show decreased uptake.

There are no other diagnosticstudies associated with sexcord/ stromal ovarian tumors

Surgery is the mainstay of treatment for sexcord/ stromal ovarian tumors. The feasibility of surgery depends on the stage of the tumor at diagnosis. Both benign and malignant ovarian sex cord-stromal tumors are managed surgically. Treatment in all postmenopausal and pre-menopausal women with bilateral involvement of ovaries includes total abdominal hysterectomy and bilateral salpingo-oophorectomy (TAH-BSO).Unilateral salpingo-oophorectomy (USO) with preservation of the contralateral ovary and the uterus is considered to be adequate surgical treatment for the majority of pre-menopausal patients with granulosa cell tumors.BEP(bleomycin, etoposide, cisplatin) is the most accepted chemotherapy regimen even for recurrent disease that is refractory to hormone therapy. Hormone treatment is usually added for advanced granulosa cell tumors(GrCTs), given their frequent association with oestrogen dependence and usually indolent course.

There are no established measures for the primary prevention of sexcord/ stromal ovarian tumors

There are no established measures for the secondary prevention of sexcord/ stromal ovarian tumors

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Maneesha Nandimandalam, M.B.B.S.[2]

There is limited information about the historical perspective of sexcord/ stromal ovarian tumors.

There is limited information about the historical perspective of sexcord/ stromal ovarian tumors.

Template:WH Template:WS

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Maneesha Nandimandalam, M.B.B.S.[2]

Sexcord/ stromal ovarian tumors may be classified according to WHO into 3 subtypes: pure stromal tumors, pure sexcord tumors, mixed stromal and sexcord tumors. Histological classification of sexcord-stromal ovarian tumors includes granulosa stromal cell tumors, sertoli leydig cell tumors, gynandroblastoma, and unclassified.

WHO classification for ovarian sex cord-stromal tumors:^{[1][2][3][4][5]}

• Pure stromal tumors
  • Fibroma
  • Cellular fibroma
  • Thecoma
  • Luteinized thecoma associated with sclerosing peritonitis
  • Fibrosarcoma
  • Sclerosing stromal tumor
  • Signet-ring stromal tumor
  • Microcystic stromal tumor
  • Leydig cell tumor
  • Steroid cell tumor
  • Steroid cell tumor, malignant
• Pure sex cord tumors
  • Adult granulosa cell tumor
  • Juvenile granulosa cell tumor
  • Sertoli cell tumor
  • Sex cord tumor with annular tubules
• Mixed sex cord-stromal tumors
  • Sertoli-Leydig cell tumors
    • Well-differentiated
    • Moderately differentiated with heterologous elements
    • Poorly differentiated with heterologous elements
    • Retiform with heterologous elements
  • Sex cord-stromal tumours, NOS

WHO classification scheme for ovarian sex cord-stromal tumors^{[1][2][3][4][5]}

Types	Subtypes
Pure stromal tumors	Fibroma Cellular fibroma Thecoma Luteinized thecoma associated with sclerosing peritonitis Fibrosarcoma Sclerosing stromal tumor Signet-ring stromal tumor Microcystic stromal tumor Leydig cell tumor Steroid cell tumor Steroid cell tumor, malignant
Pure sex cord tumors	Adult granulosa cell tumor Juvenile granulosa cell tumor Sertoli cell tumor Sex cord tumor with annular tubules
Mixed sex cord-stromal tumors	Sertoli-Leydig cell tumors Well-differentiated Moderately differentiated with heterologous elements Poorly differentiated with heterologous elements Retiform with heterologous elements Sex cord-stromal tumours, NOS
NOS, not otherwise specified

Histological classification of ovarian sex cord‐stromal tumors^[6]

Types	Subtypes
Granulosa‐stromal cell tumors	Granulosa cell tumor Tumors in the thecoma‐fibroma group Thecoma Fibroma Unclassified
Sertoli–Leydig cell tumors	Well‐differentiated Sertoli cell tumor Sertoli cell tumor with lipid storage Sertoli–Leydig cell tumor (tubular adenoma with Leydig cells) Of intermediate differentiation Poorly differentiated (sarcomatoid) With heterologous elements
Gynandroblastoma	No specific subtypes
Unclassified	No specific subtypes

International Agency for Research on Cancer Histologic Groups of Ovarian Tumors

Classification from International agency for research on cancer is summarized in the table: ^[2][7][3]

Ovarian tumors
Carcinoma Serous carcinoma Mucinous carcinoma Endometrioid carcinoma Clear cell carcinoma Adenocarcinoma NOS Other specified carcinomas Unspecified carcinoma Sex cord-stromal tumors Germ cell tumors Other specified cancers (including malignant Brenner tumor, mullerian mixed tumor, and carcinosarcoma) Unspecified cancer

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief:  ; Maneesha Nandimandalam, M.B.B.S.[2]

The exact pathogenesis of sexcord/ stromal ovarian tumors is not fully understood. Mutations mainly involving FOXL2, DICER1, STK11 are involved. They are associated with ollier disease and maffucci syndrome.The microscopic pathology varies with the individual subtype of sexcord stromal ovarian tumors.

• The exact pathogenesis of sexcord/ stromal ovarian tumors is not completely understood.^[1]
• However genetic factors attribute to the pathogenesis of some subtypes of the tumors
• The pathophysiology of sexcord/ stromal ovarian tumors depends on the histological subtype.

• The recent advancing analyses have made us understand the pathophysiology of some of these tumor subtypes
• Mutations mainly involving DICER1, STK11, and FOXL2 influence the development of some of these neoplasms

FOXL2:^{[2][3][4][5][6][7][8]}

• FOXL2 is a tumor suppressor gene
• It is a member of the forkhead box (FOX) family of evolutionarily conserved transcription factors
• It plays a fundamental and crucial role in ovarian development
• It regulates the ovarian granulosa cell proliferation, follicle development and ovarian hormones synthesis
• Almost all like 97% of adult granulosa cell tumors are characterized by missense somatic point mutations (402 C→G) in FOXL2 gene
• Infact this mutation is a sensitive and specific biomarker for adult granulosa cell tumors making it a pathognomonic feature
• The phosphorylation modification of FOXL2 in particular is responsible to the growth of granulosa cell tumors
• Importantly this mutation alter’s antiproliferative pathways and also limit the apoptosis, as a result contributing to the pathogenesis of adult granulosa cell tumors
• Other factors that play an important role in the pathogenesis of granulosa cell tumors are PI3K/AKT (phosphatidylinositol-3-kinase; serine/threonine kinase), TGF-β (Transforming growth factor beta) signaling pathway, Notch signaling pathway, GATA4 and VEGF (vascular endothelial growth factor)

DICER1:^{[3][9][10][11][2][12]}

• DICER1 mutations are associated with leydig cell tumors and gynandroblastomas
• Although both germ line and somatic mutations play a role, approximately 60% of sexcord leydig cell tumors have somatic DICER1 mutations
• This particular gene DICER1 encodes for a RNA endoribonuclease that helps to cleave precursor miRNA into mature miRNAs
• DICER1 mutations are associated with a lot of tumors of which pleuropulmonary blastoma, is the most common lung tumor of infancy and early childhood
• Others are embryonal rhabdomyosarcoma of the uterine cervix, renal tumors, thyroid nodules and carcinoma, nasal chondromesenchymal hamartoma, ciliary body medulloepithelioma, pineoblastoma, and pituitary blastoma
• The above mentioned tumors typically have biallelic DICER1 mutations that are composed of a loss of function in one allele and a missense mutation in the RNase IIIb domain

STK11:

• Mutations in the STK11 gene is associated with sex cord-stromal tumors with annular tubules

• Patients with ollier disease and maffucci syndrome are associated with an increased risk of juvenile granulosa cell tumors^[10][6]
• Somatic mosaic mutations in IDH1 and IDH2 are observed
• Ollier disease includes enchondromatosis, whereas maffucci syndrome includes enchondromatosis and hemangiomas

The gross and microscopic features of the most common tumors are described below:^{[6][13][14][15][16][17][18][7][19][20][21]}

Types	Gross pathology	Microscopic pathology	Images
Adult granulosa cell tumours	They show yellowish solid or solid–cystic appearance on cut surface	It is characterised by densely cellular sheets of cells with scant cytoplasm imparting a ‘small blue cell tumour’ appearance Small cavities called Call–Exner bodies that may contain eosinophilic fluid, degenerating nuclei, hyalinised basement membrane material, or rarely basophilic fluid are seen The presence of nuclear grooves and Call–Exner bodies are often considered to be pathognomonic of AGCTs
Juvenile granulosa cell tumours	They are solid/cystic on cut sections The solid areas show a tan-yellow or greyish appearance with foci of haemorrhage and/or necrosis The cysts have serous or haemorrhagic contents	Shows a nodular or diffuse proliferation of cells embedded in an edematous or myxoid stroma Follicle-like spaces of varying sizes and shapes, containing eosinophilic or basophilic secretions, is a characteristic feature Call–Exner bodies are almost never seen
Sex cord tumour with annular tubules	They are usually solid and yellow	They are characterized by simple and complex annular (ring-shaped) tubules often with calcification They show tubules with sertoli cells arranged around one or more hyaline bodies These tubules may be scattered and admixed with normal ovarian tissue rather than forming a distinct mass especially, in patients with Peutz-Jegher syndrome
Sertoli–leydig cell tumors	They are solid, lobulated, yellow on cut surfaces Retiform tumors have a spongy sectioned surface Poorly differentiated tumors may be extensively haemorrhagic and necrotic	Well differentiated tumors are characterised by sertoli cells in a predominantly tubular pattern, and leydig cells in the intervening stroma Tumors of intermediate differentiation often show a striking so-called alveolar pattern of sertoli cells with pale cytoplasm Poorly differentiated tumors are usually dominantly sarcomatoid Retiform tumors shows elongated tubules and the stroma is focally somewhat hyalinised Heterologous elements include mucinous epithelial glands or rhabdomyosarcomatous and/or chondrosarcomatous elements
Sclerosing stromal tumor	They are mostly solid masses with yellowish foci, edema, and cystic areas	A pseudolobular pattern, admixed spindled and rounded weakly luteinised cells, Prominent typically ectatic branching staghorn-like blood vessels
Luteinised thecomas with sclerosing peritonitis	They are bilateral with abnormal in appearance due to a hypercerebriform contour often large masses having a beefy appearance with oedema and cyst formation	Microcytic change within the cellular neoplasm composed of admixed, spindled, and weakly luteinised cells Normal ovarian elements are often present between the proliferating spindle cells
Microcystic stromal tumor	They are solid and cystic with solid tissue that is tan to white to rarely yellow.	The microscopic appearance consists of three components: Microcysts (present in 60% of cases) Solid cellular areas Hyalinised fibrous stroma The microcystic pattern is characterised by small round to oval cystic spaces, focally coalescing into larger irregular channels; intracytoplasmic vacuoles are also common The solid cellular areas are usually intersected by fibrous bands and hyalineplaques
Fibroma	They are solid ovarian tumors	Spindle-shaped fibroblasts are seen
Thecoma	They appear yellow on solid sectioned surface	Lipid-laden stromal cells with pale, vaculolated cytoplasm
Fibrosarcoma	They are large unilateral masses, often with necrosis and hemorrhage	Fibromas with increased cellularity and cell proliferation (mitotic activity) They follow a malignant course

Adult granulosa cell tumors stain positive for:^{[22][23][24][25][26][27][28]}

• Inhibin
• Calretinin
• FOXL2 and
• SF-1
• WT1
• CD56

They are negative for:

• Epithelial markers CK7 and EMA
• SALL4
• CD20
• CD45

Sertoli–stromal cell tumors are positive for:

• Calretinin
• Inhibin
• SF-1
• WT1

Microcystic stromal tumor:^[19][20][29]

• CD10+
• Vimentin+
• Cyclin D1+
• Nuclear β-catenin-positive
• Inhibin–
• Calretinin–

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief:  ; Maneesha Nandimandalam, M.B.B.S.[2]

The cause of sexcord/ stromal ovarian tumors has not been identified.Mutations mainly involving FOXL2, DICER1, STK11 are involved.

The cause of sexcord/ stromal ovarian tumors has not been identified.Mutations mainly involving FOXL2, DICER1, STK11 are involved.

Template:WH Template:WS

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief:  ; Maneesha Nandimandalam, M.B.B.S.[2]

On the basis of age of onset, vaginal discharge, and constitutional symptoms, ovarian cancer must be differentiated from tubo-ovarian abscess, ectopic pregnancy, hydrosalpinx, salpingitis, fallopian tube carcinoma, uterine leiomyoma, choriocarcinoma, leiomyosarcoma, pregnancy, appendiceal abscess, appendiceal neoplasm, diverticular abscess, colorectal cancer, pelvic kidney, advanced bladder cancer, and retroperitoneal sarcoma.

On the basis of age of onset, vaginal discharge, and constitutional symptoms, ovarian cancer must be differentiated from tubo-ovarian abscess, ectopic pregnancy, hydrosalpinx, salpingitis, fallopian tube carcinoma, uterine leiomyoma, choriocarcinoma, leiomyosarcoma, pregnancy, appendiceal abscess, appendiceal neoplasm, diverticular abscess, colorectal cancer, pelvic kidney, advanced bladder cancer, and retroperitoneal sarcoma.

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	Follicular cysts [1]	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 [2][3][4]	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 [5][6][7][8]	>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 [9][10][11]	>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 [12][13][14]	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 [15][16][17][18]	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 [19][20]	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 [21][22][23]	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 [24][25][26]	>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 [27][28][29]	>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 [30][31][32][33]	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 [34][35]	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 [36][37]	>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 [38][39]	>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 [40][41][42][43]	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 [44]	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 [45][46][47]	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 [48]	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 [49]	>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 [50][51]	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 [52][53][54][55]	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 [56][57][58][59][60]	>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 [61]	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 [62]	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 [63][64][65][66][67]	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

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief:  ; Maneesha Nandimandalam, M.B.B.S.[2]

The yearly adjusted incidence rate is approximately 2 per 1,000,000 women for sexcord-stromal ovarian tumors(SCSTs). The mortality rate has gradually been declining from1976 (10.0 per 100,000) and 2015 (6.7 per 100,000) by 33%. The age at presentation varies depending on the subtypes of sexcord-stromal ovarian tumors. Sexcord-stromal ovarian tumors(SCSTs) have more predilection in women of Caucasian background. Rates are highest among Whites, intermediate for Hispanics, and lowest among Blacks, and Asian people. Intrestingly there has been increases in incidence and mortality rates in less developed countries with recent economic growth and lifestyle changes.

• Ovarian sex cord-stromal tumors are very uncommon neoplasms that represent only 7% of all ovarian tumors^[1][2][3][4]
• The yearly adjusted incidence rate is approximately 2 per 1,000,000 women for sexcord-stromal ovarian tumors(SCSTs)
• Overall ovarian cancer incidence shows declining trends from 1985 (16.6 per 100,000) to 2014 (11.8 per 100,000) by 29%

• The mortality rate has gradually been declining from1976 (10.0 per 100,000) and 2015 (6.7 per 100,000) by 33%^[3][5][6][7]
• Improvements in either early detection or in treatment did not contribute to the decline in mortality because there was no reduction in ovarian cancer case-fatality at 12 years
• A decline in the incidence rate of ovarian cancer parallels the decline in mortality which in turn may be due to a decreased proportion of ovarian cancer patients who die from their cancer (case-fatality)

The age at presentation varies depending on the subtypes of sexcord-stromal ovarian tumors:^[8]

Fibromas:

• Although they can present at any age, the mean age of occurrence is in the late forties

Thecomas:

• They are more likely to occur in postmenopausal women

Sclerosing stromal tumor(SSTs):

• SSTs are more likely to occur in young women
• Approximately 80% of the reported cases are under 30 years of age
• A few cases have been reported in premenarchal girls, although SSTs most commonly occur after menarche

Steroid cell tumors:

• The average age of presentation is 43 years

Adult and juvenile granulosa cell tumors:

• The incidence of adult granulosa cell tumors peaks in early postmenopausal women
• The juvenile form occurs predominantly in children and young women (<30 years)

• Racial predilection do exist for sexcord-stromal ovarian tumors^[2][9]
• Racial differences in incidence and mortality within the United States are similar to the observed international variation
• Sexcord-stromal ovarian tumors(SCSTs) have more predilection in women of Caucasian background
• Rates are highest among Whites, intermediate for Hispanics, and lowest among Blacks, and Asian people

• The incidence and mortality has gradually declined since the 1990s in most developed countries, largely including North America and Europe
• Intrestingly there has been increases in incidence and mortality rates in less developed countries with recent economic growth and lifestyle changes
• In China, this increase is obvious only among rural women rather than those in more developed urban areas

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief:  ; Maneesha Nandimandalam, M.B.B.S.[2]

Common risk factors in the development of sexcord/ stromal ovarian tumors include preterm birth, high gonadotrophin levels, increasing age at first pregnancy, obese and non-white women

There is very little data regarding the risk factors of sexcord-stromal ovarian tumors, however given below are some of the important risk factors for the development of sexcord-stromal ovarian tumors:^{[1][2][3][4][5]}

• Preterm birth is a risk factor for developing sex cord-stromal tumors
• High gonadotropin levels in preterm girls could mediate disease risk by the proliferative and steroidogenic effects of FSH and LH on granulosa and theca cells
• Maternal sex-cord stromal tumors are associated with high levels of androgens during pregnancy ( indicating that elevated androgens may also play a role in the pathogenesis of sex-cord stromal tumors)
• Pregnancy is a risk factor especially with increasing age at first term pregnancy
• There is evidence suggesting that granulosa cell tumors are more likely to occur in: ^[6]
  • Nonwhite
  • Obese
  • Women with family history of breast or ovarian cancer

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief:  ; Maneesha Nandimandalam, M.B.B.S.[2]

There is insufficient evidence to recommend routine screening for sexcord/ stromal ovarian tumors. According to the US Preventive Services Task Force(USPSTF) , screening for sexcord/ stromal ovarian tumors is not recommended in asymptomatic women

• The US Preventive Services Task Force(USPSTF) recommends against screening for ovarian cancer in asymptomatic women^[1][2]
• The USPSTF found that screening with either transvaginal ultrasound or testing for the serum tumor marker cancer antigen 125 (CA-125) or a combination of both does not reduce ovarian cancer mortality

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: ; Maneesha Nandimandalam, M.B.B.S.[2]

The symtoms of sexcord/ stromal ovarian tumors include Adnexal mass, Abdominal & pelvic symptoms, Bloating, Urinary urgency or frequency, Dysphagia(difficulty)eating) or feeling full quickly, Pelvic or abdominal pain. Common complications of sexcord/ stromal ovarian tumors include malignant pleural effusion,bowel obstruction,ascites. The prognosis varies with the subtypes of tumor. Most sexcord-stromal ovarian tumors present at a low tumor stage and also prognosis in these patients is excellent.

• The symptoms of sexcord/ stromal ovarian tumors usually develop in the second/ third/ fourth decade of life, and start with symptoms such as:^[1]
  • Adnexal mass
  • Abdominal & pelvic symptoms
  • Bloating
  • Urinary urgency or frequency
  • Dysphagia(difficulty eating) or feeling full quickly
  • Pelvic or abdominal pain

• Common complications of sexcord/ stromal ovarian tumors include:
  • Malignant pleural effusion
  • Bowel obstruction
  • Ascites

• Depending on the extent of the tumor at the time of diagnosis, the prognosis may vary. However, the prognosis is generally regarded as excellent^{[2][3][4][5][3][6]}
• The prognosis varies with the subtypes of tumor
• Most sexcord-stromal ovarian tumors present at a low tumor stage and also prognosis in these patients is excellent
• The two important predictors for improved survival in patients with ovarian sex cord stromal tumors are young age and early-stage disease
• Patients with juvinile granulosa cell tumors(JGCT) and sertoli-Leydig cell tumors (SLCTs) show greater mitotic activity than all other histologic types
• The presence of greater mitotic activity is associated with a particularly poor prognosis among patients with juvinile granulosa cell tumors(JGCT) and sertoli-Leydig cell tumors (SLCTs)
• Other independent prognostic factors in adult granulosa cell tumors include mitotic index, lymphovascular invasion, cellular atypia, and absence of Call-Exner bodies
• Sertoli-Leydig cell tumors have a 70 to 90 percent five-year survival overall and is mainly related to the stage and degree of histologic differentiation

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