Ovarian carcinomaOvarian carcinomaBy By

Dr.Dr. Khattab KAEO Khattab KAEO

ProfProf. and Head of Obstetrics & . and Head of Obstetrics & GynaeGynaecology Department cology Department

FacFaculty of Medicine, Al-Azhar ulty of Medicine, Al-Azhar UnivUniversity, ersity, DamiettaDamietta

Incidence:Incidence: 1/10 000; 1/10 000; 1.35/10 000 among 1.35/10 000 among Ashkenazi Jews born in Ashkenazi Jews born in Europe & America. Ovarian Europe & America. Ovarian cancer = 4% of cancer in cancer = 4% of cancer in women. 25% of all ovarian women. 25% of all ovarian neoplasms are malignant. neoplasms are malignant.

The incidence is high in The incidence is high in developed countries. developed countries.

Prognosis:Prognosis: 2/3 of cases are diagnosed in 2/3 of cases are diagnosed in stage III or IV. This could be attributed to stage III or IV. This could be attributed to the facts of vague symptoms and lack of the facts of vague symptoms and lack of adequate screening.adequate screening.

1/3 of stage I cases are upgraded to stage 1/3 of stage I cases are upgraded to stage III. III.

All these facts explain the poor survival rate. All these facts explain the poor survival rate. Ovarian carcinoma is the 4th most Ovarian carcinoma is the 4th most

common cause of death in women in common cause of death in women in Western countries. Western countries.

In the USA ovarian cancer is the 5th most In the USA ovarian cancer is the 5th most common cancer & is the 4th most common cancer & is the 4th most common cause of death due to cancer. common cause of death due to cancer.

Epithelial ovarian carcinoma is the most Epithelial ovarian carcinoma is the most frequent cause of death from frequent cause of death from gynaecological malignancy. gynaecological malignancy.

Risk factors:- Age: Incidence peaks between ages of 65 and 75 years (1 in 400; at the age of 50, the prevalence is 1:1500). Ovarian neo-plasms occurring in the childhood up to the early twenties are probably malignant (non-epithelial). Germ cell tumour is the most frequent malignant tumor in children. -Nulliparity. - History of breast or endometrial cancer. - Higher consumption of animal fat, proteins and whole milk. - The use of infertility drugs for >1 y. The use of CC for >1 year carries a 10-x risk.

- Family history: Only 5% are due to hereditary factors - Family history: Only 5% are due to hereditary factors (30% among Ashkenazi Jews for ex). It is an auto-(30% among Ashkenazi Jews for ex). It is an auto-somal dominant disease. Syndromes somal dominant disease. Syndromes includeinclude BRCA1 BRCA1 or 2 mutation & Hereditary NonPolyposis Colorectal or 2 mutation & Hereditary NonPolyposis Colorectal Cancer Syndrome (HNPCC, Lynch Syndrome of Cancer Syndrome (HNPCC, Lynch Syndrome of familial breast, colo-rectal & ovarian cancer). familial breast, colo-rectal & ovarian cancer). BRCA1 gene is on 17q. BRCA1 gene is on 17q.

Ovarian tumors, not epithelial, arise in some other rare Ovarian tumors, not epithelial, arise in some other rare syndromessyndromes e.g. Peutz-Jagher syndrome (granulosa e.g. Peutz-Jagher syndrome (granulosa cell tumours, Brenner tumours & dysgerminoma), cell tumours, Brenner tumours & dysgerminoma), Gorlin syndrome (fibromas) & gonadal dysgenesis Gorlin syndrome (fibromas) & gonadal dysgenesis (gonadoblastoma). (gonadoblastoma).

Hereditary ovarian or breast cancer = ≥2 affected 1st Hereditary ovarian or breast cancer = ≥2 affected 1st degree relatives or a family pedigree indicative of degree relatives or a family pedigree indicative of autosomal inheritance. One affected relative = 2-3-autosomal inheritance. One affected relative = 2-3-x increase in relative risk. 2 affected 1st degree x increase in relative risk. 2 affected 1st degree relatives = chance increases from 1:70 to 1:40. relatives = chance increases from 1:70 to 1:40. BRCA1 is found in almost all families with both BRCA1 is found in almost all families with both breast & ovarian cancer & in 40% of families with breast & ovarian cancer & in 40% of families with breast cancer alone. 80% of affected individuals breast cancer alone. 80% of affected individuals develop malignancy. develop malignancy.

The mean age of onset (50y) in BRCA1 mutations is 5 The mean age of onset (50y) in BRCA1 mutations is 5 years younger (risk begins to rise in the late 30s). years younger (risk begins to rise in the late 30s).

Protective factors:Protective factors:

1- Parity. 1- Parity.

2- There is inverse association with age at first 2- There is inverse association with age at first birth!birth!

3- The use of COCs (≥5y) substantially reduces 3- The use of COCs (≥5y) substantially reduces the risk of sporadic & hereditary ovarian the risk of sporadic & hereditary ovarian carcinoma. carcinoma.

4- Tubal ligation or hysterectomy 4- Tubal ligation or hysterectomy reduced risk reduced risk through reduced contamination of peritoneum through reduced contamination of peritoneum & ovary and possibly through decreased ovul. & ovary and possibly through decreased ovul.

5- Breast feeding suppresses ovulation. 5- Breast feeding suppresses ovulation.

6- Higher consumption of dietary fibres, vit A & C 6- Higher consumption of dietary fibres, vit A & C

7- Infection with mumps virus! 7- Infection with mumps virus!

Hypotheses:Hypotheses:

Fathalla postulated repeated minor trauma to the Fathalla postulated repeated minor trauma to the epithelial surface. In animals, proliferations of epithelial surface. In animals, proliferations of epithelium after ovulation and mitotic figures near epithelium after ovulation and mitotic figures near the site of ovulation have been shown. Factors that the site of ovulation have been shown. Factors that suppress ovulation reduce the risk of ovarian cancer suppress ovulation reduce the risk of ovarian cancer Risk is increased with fertility drugs. Risk is increased with fertility drugs.

The Gn hypothesis postulates exposure of the ovary to The Gn hypothesis postulates exposure of the ovary to continuous high levels of Gn. Parity & COCs have a continuous high levels of Gn. Parity & COCs have a protective effect Risk is increased with fertility drugsprotective effect Risk is increased with fertility drugs

The pelvic contamination theory postulates that patho-The pelvic contamination theory postulates that patho-gens may contaminate the ovary after passage gens may contaminate the ovary after passage through the genital tract. through the genital tract.

BRCA1 & 2 function as tumour suppressor genes. They BRCA1 & 2 function as tumour suppressor genes. They encode proteins necessary for repair of DNA damage encode proteins necessary for repair of DNA damage Mutations Mutations uncontrolled cell growth uncontrolled cell growth cancers in cancers in the breast, tubes, ovary & peritoneum. the breast, tubes, ovary & peritoneum.

STAGING:STAGING: FIGO. FIGO. Stage I Ltd to the ovary. Stage I Ltd to the ovary.

IA Ltd to 1 ovary; no tumor on the surf.; no ascites; IA Ltd to 1 ovary; no tumor on the surf.; no ascites; cap. is intact. cap. is intact.

IB Ltd to both ovaries + same conditions. IC IB Ltd to both ovaries + same conditions. IC Either IA or IB with tumour on the surface, rup-tured Either IA or IB with tumour on the surface, rup-tured cap or malign. ascites/+ve peritoneal washing. cap or malign. ascites/+ve peritoneal washing.

Stage II Pelvic extension. Stage II Pelvic extension. IIA Extension to the uterus or tubes. IIB IIA Extension to the uterus or tubes. IIB

Other pelvic extensions. IIC Other pelvic extensions. IIC Either IIA or IIB with tumour on the surf; rup-tured Either IIA or IIB with tumour on the surf; rup-tured cap or malign ascites /+ve peritoneal washing. cap or malign ascites /+ve peritoneal washing.

Stage III Peritoneal implants outside the pelvis Stage III Peritoneal implants outside the pelvis +ve LN; &/or superf. liver M +ve LN; &/or superf. liver M IIIA Microscopic seeding of peritoneal surfaces. IIIA Microscopic seeding of peritoneal surfaces. IIIB Histological implants of IIIB Histological implants of peritoneal surfaces peritoneal surfaces <2cm<2cm IIIC Same IIIC Same implants >2cm.implants >2cm.

Stage IV Distant metastasis including liver Stage IV Distant metastasis including liver parenchyma, pleural effusion, etc.parenchyma, pleural effusion, etc.

WHO Histological Classification: WHO Histological Classification:

I- Epithelial tumours: I- Epithelial tumours: Serosal tumours: Serous cyst adenocarcinoma.Serosal tumours: Serous cyst adenocarcinoma.

Constitutes 50% of all epithelial malignancy & Constitutes 50% of all epithelial malignancy & 40% of malignant ovarian tumours (the com 40% of malignant ovarian tumours (the com monest ovarian carcinoma). Bilateral in 50% of monest ovarian carcinoma). Bilateral in 50% of cases Presents as stage III in 50% of cases Presents as stage III in 50% of casescases Ascites Ascites is always present. is always present. Psammoma bodiesPsammoma bodies are are encountered in >30% of serous tumours encountered in >30% of serous tumours (characteristic). They are microcrystals of bone (characteristic). They are microcrystals of bone similar to calcium phosphate crystals formed similar to calcium phosphate crystals formed intracellularly and are consequences of intracellularly and are consequences of dystrophic calcification. Usually endophytic dystrophic calcification. Usually endophytic

Most are partially cystic & partially solid. Either Most are partially cystic & partially solid. Either smooth or with papillary projections. smooth or with papillary projections.

Mucinous carcinoma: Bilateral in 5-10%.Mucinous carcinoma: Bilateral in 5-10%.

Clear cell carcinoma: Clear cell carcinoma: Characterised by Hob-Characterised by Hob-nail cells (nail cells (polygonalpolygonal cellscells withwith clear cytoplasm). clear cytoplasm). It contains tubules, glands, papillae & cysts. It contains tubules, glands, papillae & cysts. Bilateral in 40%. 50% are stage I. Bilateral in 40%. 50% are stage I.

Endometrioid carcinoma: Up to 30% Endometrioid carcinoma: Up to 30% coexist with endometrial adenocar-coexist with endometrial adenocar-cinoma & closely resembles it. cinoma & closely resembles it. 10% coexist with endometriosis 10% coexist with endometriosis and arises in endometrioma. The and arises in endometrioma. The vast majority are vast majority are unilateralunilateral & & almost always almost always stage Istage I. Attacks of . Attacks of painpain, unusual with ovarian cancer, , unusual with ovarian cancer, are common. Usually cystic and are common. Usually cystic and chocolate brown in colour If such a chocolate brown in colour If such a cyst ruptures spontaneously, cyst ruptures spontaneously, malignancy should be suspected. malignancy should be suspected.

Brenner tumours arise in epithelial Brenner tumours arise in epithelial cells of Wolffian origin. cells of Wolffian origin.

Transitional cell carcinoma: Brenner tumour Transitional cell carcinoma: Brenner tumour closely resembles low-grade transitional cell closely resembles low-grade transitional cell carcinoma. Transitional cell carcinoma differs carcinoma. Transitional cell carcinoma differs in lacking the benign Brenner component, in lacking the benign Brenner component, are more likely to spread beyond the ovary are more likely to spread beyond the ovary and more likely to result in death even if and more likely to result in death even if confined to the ovary. It also lacks the pro-confined to the ovary. It also lacks the pro-minent stromal calcifications present in most minent stromal calcifications present in most malignant Brenner tumours. In spite of that malignant Brenner tumours. In spite of that transitional cell carcinoma is more sensitive transitional cell carcinoma is more sensitive to chemotherapy and has a more favourable to chemotherapy and has a more favourable survival than serous carcinoma. survival than serous carcinoma.

Mixed epithelial tumours. Mixed epithelial tumours.

Undifferentiated tumours. Undifferentiated tumours.

Unclassified epithelial tumours. Unclassified epithelial tumours.

II- Stromal gonadal (Sex cord stromal) tumours II- Stromal gonadal (Sex cord stromal) tumours Previously called mesenchymoma. 90% are Previously called mesenchymoma. 90% are thecoma and granulosa cell tumours. thecoma and granulosa cell tumours. InhibinInhibin (particularly (particularly unit) distinguishes them from unit) distinguishes them from non-sex cord tumours.non-sex cord tumours.

Granulosa cell tumours constitute 10% of all solid Granulosa cell tumours constitute 10% of all solid malignant ovarian tumours and 70% of sex cord-malignant ovarian tumours and 70% of sex cord-stromal tumours. They have a good prognosis, but stromal tumours. They have a good prognosis, but 0.6-6% of cases is associated with endometrial 0.6-6% of cases is associated with endometrial adenocarcinoma. It is a hormonally active tumour adenocarcinoma. It is a hormonally active tumour (most tumours secrete oestrogen; few produce and- (most tumours secrete oestrogen; few produce and- rogen), may be malignant or semi-malignant. rogen), may be malignant or semi-malignant. Sertoli-Leydig cell tumour (Androblastoma): Rare Sertoli-Leydig cell tumour (Androblastoma): Rare and occurs in young adult females. The well-differen and occurs in young adult females. The well-differen tiated tumour may be of the Sertoli cell type, Leydig tiated tumour may be of the Sertoli cell type, Leydig cell type, Sertoli-Lydig cell type or Sertoli cell type cell type, Sertoli-Lydig cell type or Sertoli cell type with lipid storage Moderately & poorly-differentiated with lipid storage Moderately & poorly-differentiated types also exist. The tumour may contain cartilage & types also exist. The tumour may contain cartilage & GIT epithelium (heterogenous type). It may secrete GIT epithelium (heterogenous type). It may secrete testosterone (rarely oestrogen) in 25% of cases The testosterone (rarely oestrogen) in 25% of cases The androgen-secreting tumor is called arrhenoblastoma androgen-secreting tumor is called arrhenoblastoma The tumour usually appears small white or yellowish The tumour usually appears small white or yellowish It is usually of low-grade malignancy. The tumour is It is usually of low-grade malignancy. The tumour is mainly composed of tubules lined by cuboidal cells mainly composed of tubules lined by cuboidal cells with interstitial cells of Leydig (containing the rod-with interstitial cells of Leydig (containing the rod-shaped structures, crystalloids of Reinke) inbetween shaped structures, crystalloids of Reinke) inbetween the tubules. the tubules.

GynandroblastomaGynandroblastoma

III- Germ cell tumoursIII- Germ cell tumoursConstitute 10% of ovarian tumours with Constitute 10% of ovarian tumours with

4% are malignant. They are more pre-4% are malignant. They are more pre-valent in children & adolescents. Under valent in children & adolescents. Under the age of 20, germ cell tumours = 60-the age of 20, germ cell tumours = 60-70% of ovarian tumours with 33% are 70% of ovarian tumours with 33% are malignant (under the age of 20, 85% malignant (under the age of 20, 85% are malignant). Secrete AFP & hCG. are malignant). Secrete AFP & hCG. Either dysgerminoma or embryonal carcin. Either dysgerminoma or embryonal carcin. The latter is either embryonic (polyembry-The latter is either embryonic (polyembry-oma or teratoma) or extra-embryonic (chorio oma or teratoma) or extra-embryonic (chorio carcinoma or endodermal sinus tumour).carcinoma or endodermal sinus tumour). The following is the WHO histologic The following is the WHO histologic classification of germ cell tumours: classification of germ cell tumours:

i- Teratoma. i- Teratoma. A- Immature teratomas may be solid &/ or cystic. It is A- Immature teratomas may be solid &/ or cystic. It is

composed of both embryonal & adult tissues from all composed of both embryonal & adult tissues from all 3 germ layers. Mesodermal elements often predomin 3 germ layers. Mesodermal elements often predomin depending on maturity of the tumor. Endodermal depending on maturity of the tumor. Endodermal elements may be represented by tubules lined with elements may be represented by tubules lined with columnar epithelium. Ectodermal elements usually columnar epithelium. Ectodermal elements usually consist of hair, teeth & neural tissue, contained consist of hair, teeth & neural tissue, contained within loose stroma. within loose stroma.

It is reported in ages ranging from 14 months to 40 y It is reported in ages ranging from 14 months to 40 y 80% presents as a palpable pelvic/abdominal mass, 80% presents as a palpable pelvic/abdominal mass, mostly unilateral, firm, irregular, 5-35 cm with multi mostly unilateral, firm, irregular, 5-35 cm with multi ple cystic spaces 0.5-10 cm diameter each with ple cystic spaces 0.5-10 cm diameter each with areasareas of haemorrhage & necrosis. Neural tissue may be of haemorrhage & necrosis. Neural tissue may be visible grossly. Fever & leukocytosis are noted in visible grossly. Fever & leukocytosis are noted in 25% of cases. Haematogenous metastases are rare. 25% of cases. Haematogenous metastases are rare. Malignant teratoma is unilateral. Malignant teratoma is unilateral.

Unilateral salpingo-oophorectomy may be sufficient Unilateral salpingo-oophorectomy may be sufficient for stage I tumors; VAC chemotherapy, (over a 12-for stage I tumors; VAC chemotherapy, (over a 12-month period) is added for grade 3 and stage II or III month period) is added for grade 3 and stage II or III tumours Rupture before or during surgery carries an tumours Rupture before or during surgery carries an 80% risk of recurrence. 80% risk of recurrence.

B- Mature teratomas may be solid (grade 0) or cystic. B- Mature teratomas may be solid (grade 0) or cystic. a- >95% of teratomas are mature (adult) cystic teratomas (dermoids).a- >95% of teratomas are mature (adult) cystic teratomas (dermoids).

Epidermal elements often predominate. It may be found in neo Epidermal elements often predominate. It may be found in neo nates, but predominates in the reproductive years. Size ranges nates, but predominates in the reproductive years. Size ranges from 4 mm to 15 cm, usually unilocular with thick greasy fluidy from 4 mm to 15 cm, usually unilocular with thick greasy fluidy sebum & desquamated cells (mucinous intestinal sebum & desquamated cells (mucinous intestinal oror clear clear watery brain cells). There may be laminated pellets of lipids. watery brain cells). There may be laminated pellets of lipids. Teeth in 30%. Bilateral in 12%. It tends to have a long pedicle Teeth in 30%. Bilateral in 12%. It tends to have a long pedicle (torsion is the most common complication). The pedicle may (torsion is the most common complication). The pedicle may dissolute (dissolute ( parasitic dermoid). Wall is thick and gray, lined by parasitic dermoid). Wall is thick and gray, lined by stratified squamous epithelium. There may be a projecting area stratified squamous epithelium. There may be a projecting area in the cavity known as Rokitansky's protuberance or the in the cavity known as Rokitansky's protuberance or the dermoid pro-cess. Strange contents include rudimentary fetal dermoid pro-cess. Strange contents include rudimentary fetal tissue such as cranium & brain, mandible, arm & forearm, ribs, tissue such as cranium & brain, mandible, arm & forearm, ribs, pelvic bones, vertebrae & phalanges (complex dermoid). Cystic pelvic bones, vertebrae & phalanges (complex dermoid). Cystic teratomas tend to be asymptomatic; however, 47% of patients teratomas tend to be asymptomatic; however, 47% of patients complains of pain, while 15% complains of a mass & 15% complains of pain, while 15% complains of a mass & 15% complains of bleeding. Rupture is rare; chemical peritonitis complains of bleeding. Rupture is rare; chemical peritonitis may occur which may be catastrophic Peculiarly, rupture may may occur which may be catastrophic Peculiarly, rupture may result in expulsion of teeth, bones and hair from the rectum or result in expulsion of teeth, bones and hair from the rectum or bladder. A small defect may result in chronic or intermittent bladder. A small defect may result in chronic or intermittent abdominal pain and granulomatous reaction with lipid-laden abdominal pain and granulomatous reaction with lipid-laden macrophages, lympho- cytes, plasma cells & foreign body giant macrophages, lympho- cytes, plasma cells & foreign body giant cells. cells.

b- Dermoid cyst with malignant transformation; 2% of benign cys b- Dermoid cyst with malignant transformation; 2% of benign cys tic teratomas contain a malignant component Extirpation of the tic teratomas contain a malignant component Extirpation of the tumor with conservation of the ovary or hysterectomy with uni tumor with conservation of the ovary or hysterectomy with uni lateral or BSO may be chosen according to patient's age & fert. lateral or BSO may be chosen according to patient's age & fert.

C- monodermal (highly specialised) teratoma. C- monodermal (highly specialised) teratoma. a- struma ovarii. 5-10% of cystic teratomas. Dia-a- struma ovarii. 5-10% of cystic teratomas. Dia-

gnosis is made if thyroid tissue occupies all or gnosis is made if thyroid tissue occupies all or most of the tumour or if thyroid tissue is recog most of the tumour or if thyroid tissue is recog nised grossly. The tumor is smooth, rounded & nised grossly. The tumor is smooth, rounded & the cut surface has a glistening amber the cut surface has a glistening amber appappearanceearance

b- carcinoid (argentaffinoma) is a serotonin-prod b- carcinoid (argentaffinoma) is a serotonin-prod ucing tumour arises in association with ucing tumour arises in association with dermoid.dermoid. The typical carcinoid syndrome consists of patchy cyano The typical carcinoid syndrome consists of patchy cyano sis, flushing, diarrhea, colic, oedema, hypertension & sis, flushing, diarrhea, colic, oedema, hypertension & car diac failure due to tricuspid valve lesion. Most car diac failure due to tricuspid valve lesion. Most ovarian carcinoids are of the insular type (ovarian carcinoids are of the insular type (== those those derived from the mid-gut; solid islands of cells derived from the mid-gut; solid islands of cells separated by a dense fibrous separated by a dense fibrous stromastroma Trabecular Trabecular carcinoids are also reported (carcinoids are also reported (== those derived from the those derived from the fore & hind gut; longway ribbons of cells separated by fore & hind gut; longway ribbons of cells separated by loose fibrous stroma).loose fibrous stroma). The larger the carcinoid The larger the carcinoid component, the more solid is the tumor. The component, the more solid is the tumor. The median age for the insular & the tra becular median age for the insular & the tra becular types is 57 & 47 y (well above that for dermoid. types is 57 & 47 y (well above that for dermoid. The median diameter is 10 cm. Symp-toms The median diameter is 10 cm. Symp-toms regress after removal of the tumor. The regress after removal of the tumor. The optimal ttt is TAHBSO. In the childbearing per-optimal ttt is TAHBSO. In the childbearing per-iod however, a unilateral SO may suffice, but iod however, a unilateral SO may suffice, but the contralateral ovary should be biopsed. the contralateral ovary should be biopsed.

c- struma ovarii and carcinoid (commonly of the trabecular type). d- others.

ii- Dysii- Dysgermgerminoma: The commonest malignant germ cell neoplasm inoma: The commonest malignant germ cell neoplasm (=48%)(=48%) Solid,Solid, usually ovoid or lobular, of rubbery consistency & usually ovoid or lobular, of rubbery consistency & greyish colour. Morphologically, it is identical to testicular greyish colour. Morphologically, it is identical to testicular seminoma (both arise from the primordial germ cells of the in-seminoma (both arise from the primordial germ cells of the in-defferent stage of gonadogenesis). About 15 cm (ranges from 3 defferent stage of gonadogenesis). About 15 cm (ranges from 3 cm to a size filling the abdomen), with a cm to a size filling the abdomen), with a smoothsmooth cap, with cap, with necrosis & hage in 50% It secretes necrosis & hage in 50% It secretes hCGhCG, but may be estrogenic , but may be estrogenic less commonly androgenic. It is bilateral in 15% of cases Micro less commonly androgenic. It is bilateral in 15% of cases Micro scopically, it consists of scopically, it consists of masses of large clear epithelial cellsmasses of large clear epithelial cells separated by fine connective tissue infiltrated by lymphocytes. separated by fine connective tissue infiltrated by lymphocytes. The cells are arranged in cords or in an alveolar pattern. The The cells are arranged in cords or in an alveolar pattern. The majority of cases are diagnosed before the age of 30. Many majority of cases are diagnosed before the age of 30. Many appear relatively benign and do not recur. It is both appear relatively benign and do not recur. It is both radio-radio- & & chemo-sensitivechemo-sensitive. The optimal therapy must be based on the . The optimal therapy must be based on the operative findings and a histologic examination. Unilateral SO operative findings and a histologic examination. Unilateral SO can be adopted to unilateral cases in young nullipara, but only can be adopted to unilateral cases in young nullipara, but only in conjunction with peritoneal saline irrigation for cytologic in conjunction with peritoneal saline irrigation for cytologic study, wedge biopsy of the contralateral ovary, omental biopsy study, wedge biopsy of the contralateral ovary, omental biopsy and aortic node sampling at the level of the duodenum. Any and aortic node sampling at the level of the duodenum. Any palpable nodes should be removed. Bilaterality does not affect palpable nodes should be removed. Bilaterality does not affect survival, while marked lymphocytic infiltration or a granulomat survival, while marked lymphocytic infiltration or a granulomat ous response are associated with a favourable outcome. The ous response are associated with a favourable outcome. The most important microscopic determinant of survival is the pre- most important microscopic determinant of survival is the pre- sence of other germ cell elements. If >1/3 of a stage I t is com sence of other germ cell elements. If >1/3 of a stage I t is com posed of endodermal sinus tumour, choriocarcinoma or G 3 im- posed of endodermal sinus tumour, choriocarcinoma or G 3 im- mature teratoma, the prognosis would be poor. mature teratoma, the prognosis would be poor.

iii Endodermal sinus tumor: = 20% of germ cell t It iii Endodermal sinus tumor: = 20% of germ cell t It is highly malignant is highly malignant and affects children & young adults and affects children & young adults (14 mo to 45 y. It is 2nd to dysgerminoma before the age (14 mo to 45 y. It is 2nd to dysgerminoma before the age of 20y).of 20y). Pain is present in 77% of cases, abdom. mass in Pain is present in 77% of cases, abdom. mass in 27% & fever in 24%. 27% & fever in 24%. Average size is 10-20 cm, Average size is 10-20 cm, unilateral, the cut surface is yellowish tan or gray unilateral, the cut surface is yellowish tan or gray with areas of necrosis or hage & Swiss cheese with areas of necrosis or hage & Swiss cheese small cysts. It may be found as a broad ligament small cysts. It may be found as a broad ligament tumor when some germ cells did not complete tumor when some germ cells did not complete migration from the y s to the gonadal site The migration from the y s to the gonadal site The classic microscopic pattern is reticular (consists classic microscopic pattern is reticular (consists of a network of sinuses lined by cub-oidal cells of a network of sinuses lined by cub-oidal cells with scanty cytoplasm & occasional hobnail with scanty cytoplasm & occasional hobnail cells). The characteristic appearance is cells). The characteristic appearance is Schiller Schiller Duval bodyDuval body, found in 75% of the t; it is villus-like , found in 75% of the t; it is villus-like structure with central bl v (y s endo- derm structure with central bl v (y s endo- derm surrounding a capillary). There ± intra & surrounding a capillary). There ± intra & intercellular hyaline droplets (with AFP found in intercellular hyaline droplets (with AFP found in them them The tumor produces The tumor produces AFPAFP Although Although very chemo very chemo sensitivesensitive, prognosis is poor (fatality rate = 90% & peri-, prognosis is poor (fatality rate = 90% & peri-toneal metastasis is encountered after removal of a well toneal metastasis is encountered after removal of a well encapsulated tumor. At the best, survival rate is 17%, and encapsulated tumor. At the best, survival rate is 17%, and that is when the tumor is <10 cm, confined to the ovary & that is when the tumor is <10 cm, confined to the ovary & paradoxically if ruptured!) paradoxically if ruptured!) ttt is unilat. SO followed ttt is unilat. SO followed by VAC chemotherapy which is drama tically by VAC chemotherapy which is drama tically effective.effective.

iv- Choriocarcinoma. Extremely rare. Highly malignant iv- Choriocarcinoma. Extremely rare. Highly malignant Most commonly associated with dysgerminoma. It is Most commonly associated with dysgerminoma. It is thought that the presence of chorionic villi, thought that the presence of chorionic villi, establishesestablishes the origin of the tumour from an ovarian pregnancy! the origin of the tumour from an ovarian pregnancy! Diagnosis of pure non-gestational choriocarcinoma Diagnosis of pure non-gestational choriocarcinoma can only be made with certainty prebubetal (the can only be made with certainty prebubetal (the highhigh hCG levels stimulates ovarian stroma hCG levels stimulates ovarian stroma precocious precocious puberty or IUB. Also, the rapidly enlarging tumour is puberty or IUB. Also, the rapidly enlarging tumour is often aggravated by ascites. Rupture often aggravated by ascites. Rupture peritoneal peritoneal haemorrhage and acute surgical emergency). haemorrhage and acute surgical emergency). Choriocarcinoma is always unilateral. The opposite Choriocarcinoma is always unilateral. The opposite ovary is frequently enlarged by theca-lutein cysts or ovary is frequently enlarged by theca-lutein cysts or shows marked stromal luteinisation. The surface is shows marked stromal luteinisation. The surface is nodular with haemorrhagic tissue within a thin caps. nodular with haemorrhagic tissue within a thin caps. The tumor is extremely friable with areas of necrosis The tumor is extremely friable with areas of necrosis and cavitation. Microscopically, it is composed of syn and cavitation. Microscopically, it is composed of syn cytiotrophoblasts lining blood-filled spaces or cover cytiotrophoblasts lining blood-filled spaces or cover islands of cytotrophoblasts The tumor secretes hCG, islands of cytotrophoblasts The tumor secretes hCG, oestrogen and other trophoblastic products. It does oestrogen and other trophoblastic products. It does not respond well to conventional treatment of gesta-not respond well to conventional treatment of gesta-tional choriocarcinoma; responds better to MAC. tional choriocarcinoma; responds better to MAC. Endodermal sinus tumour and choriocarcinoma are Endodermal sinus tumour and choriocarcinoma are called tumours of extra-embryonic tissues. called tumours of extra-embryonic tissues.

v- Embryonic carcinoma: Rare. Reported in v- Embryonic carcinoma: Rare. Reported in ages from 4-28 y. Unilateral, 10-25 cm in dia ages from 4-28 y. Unilateral, 10-25 cm in dia meter. Smooth and the cut section is yellow meter. Smooth and the cut section is yellow to gray with occasional cysts, necrosis & to gray with occasional cysts, necrosis & hagehage Sheets/nests of pleomorphic cells with round Sheets/nests of pleomorphic cells with round vesicular nuclei containing prominent vesicular nuclei containing prominent nucleoli Syncytiotrophoblastic giant cells are nucleoli Syncytiotrophoblastic giant cells are scatteredscattered in the periphery or throughout the in the periphery or throughout the stroma. Hyaline droplets characteristic of stroma. Hyaline droplets characteristic of endodermal sinus tumor and AFP are found endodermal sinus tumor and AFP are found in these cells and in the mononuclear in these cells and in the mononuclear embryonal cells. Secretes embryonal cells. Secretes hCGhCG and causes and causes precocious puberty in 50% of cases. IUB & precocious puberty in 50% of cases. IUB & amenorrhoea are re-ported too. ttt is amenorrhoea are re-ported too. ttt is unilateral SO with adjuvant chemotherapy unilateral SO with adjuvant chemotherapy (MAC or VAC). (MAC or VAC).

vi- Polyembryoma. vi- Polyembryoma. vii- Mixed tumours. vii- Mixed tumours.

IV- Mixed gonadal stromal & germ IV- Mixed gonadal stromal & germ cell tumour (Gonadoblastoma): It is cell tumour (Gonadoblastoma): It is composed of large primitive germ composed of large primitive germ cells & small granulosa cells. The cells & small granulosa cells. The latter may form Call-Exner bodies latter may form Call-Exner bodies (small rosettes) Stroma may (small rosettes) Stroma may contain Leydig-like cells. contain Leydig-like cells. Gonadoblastoma almost always Gonadoblastoma almost always occurs in gonads of occurs in gonads of inter-sexinter-sexual ual patients Y chromosome is detected patients Y chromosome is detected in >90% of cases.in >90% of cases. 80% of patients 80% of patients are phenotypically females.are phenotypically females.

V- Lipoid cell tumours: Rare tumors V- Lipoid cell tumours: Rare tumors causing causing masculinisation andmasculinisation and signs signs of of hypercorticoidismhypercorticoidism such as striae, such as striae, obesity, polycythaemia, diabetes obesity, polycythaemia, diabetes and hypertension. The tumour is and hypertension. The tumour is commonly large & commonly large & yellowishyellowish with with cells containing a high amount of cells containing a high amount of lipid The lipid The 17-ketosteroid17-ketosteroid output is output is greatly increased and the greatly increased and the excretion of 17-excretion of 17-hydroxycorticosteroids is also hydroxycorticosteroids is also raised. raised.

VI- Unspecified CT tumours: Fibro-sarcoma. VI- Unspecified CT tumours: Fibro-sarcoma. Often occurs in postmenopausal women. Often occurs in postmenopausal women. Usually lobulated, 10cm in average & the cut Usually lobulated, 10cm in average & the cut surface shows focal necrosis & cystic degene surface shows focal necrosis & cystic degene ration. Leiomyosarcoma and myxosarcoma. ration. Leiomyosarcoma and myxosarcoma.

VII- Unclassified tumours. lymphocytic, histo VII- Unclassified tumours. lymphocytic, histo cytic & Hodgkin's lymphomas. Diffuse or cytic & Hodgkin's lymphomas. Diffuse or localised. Characteristically, lymphomatous localised. Characteristically, lymphomatous tissue, does not destroy the normal architec-tissue, does not destroy the normal architec-ture & this differentiates it from carcinomas. ture & this differentiates it from carcinomas. Anaemia is out of proportion of vaginal Anaemia is out of proportion of vaginal bleeding which occurs in 20-30% of cases. bleeding which occurs in 20-30% of cases.

VIII- Metastatic tumours: Constitute 10%-20% VIII- Metastatic tumours: Constitute 10%-20% of ovarian tumours. of ovarian tumours.

Secondary carcinoma of the ovarySecondary carcinoma of the ovary1ry tumour may be in the genital tract, breast, 1ry tumour may be in the genital tract, breast, stomach or large intestine. The meta static stomach or large intestine. The meta static growths reach a large size while the 1ry gro- wth growths reach a large size while the 1ry gro- wth is small. Krukenburg's tumors are most is small. Krukenburg's tumors are most commonly due to lymphatic spread from commonly due to lymphatic spread from endoendo metrial carcinoma. The ovarian tumours are metrial carcinoma. The ovarian tumours are bilateral, of equal size, smooth & lobulatedbilateral, of equal size, smooth & lobulated. They . They remain remain freely mobilefreely mobile. The cut surface typically . The cut surface typically exhibits gelatinous necrosis & mucin -filled exhibits gelatinous necrosis & mucin -filled spaces of variable size. There are very cellular spaces of variable size. There are very cellular (hyperplastic) stroma, in which there are large (hyperplastic) stroma, in which there are large epithelial cells lying singly or in alv. The epithelial cells lying singly or in alv. The epithelial cells have a crescentic nucleus pushing epithelial cells have a crescentic nucleus pushing a clear cytoplasm full of mucin a clear cytoplasm full of mucin ((signet ringsignet ring appearance). appearance). The patient is usually between 30 & 40 y of age The patient is usually between 30 & 40 y of age with a typical presentation of a large cystic mass with a typical presentation of a large cystic mass and the majority of them succumb within 1 year and the majority of them succumb within 1 year of diagnosis.of diagnosis.

Spread Spread IMPLANTATION. Involvement of the IMPLANTATION. Involvement of the

omentum occurs in >80% of cases. omentum occurs in >80% of cases. The major route of spread is along The major route of spread is along the right paracolic gutter to the the right paracolic gutter to the undersurface of the right hemi-undersurface of the right hemi-daiaphragm, leading to obstruction daiaphragm, leading to obstruction of diaphragmatic lymphatics and of diaphragmatic lymphatics and early onset of ascites. Lymphatic early onset of ascites. Lymphatic spread occurs mainly to the para-spread occurs mainly to the para-aortic glands, sometimes to the aortic glands, sometimes to the pelvic and even inguinal groups.pelvic and even inguinal groups.

PresentationPresentation- Family history of ovarian, breast or colorectal Family history of ovarian, breast or colorectal carcinoma. Ask of which histologic type? Ask carcinoma. Ask of which histologic type? Ask about the ethnic origin.about the ethnic origin.

- Early symptoms are often Early symptoms are often non-specificnon-specific such as such as abdominal discomfort, nausea, gas, etc. abdominal discomfort, nausea, gas, etc.

- As the tumor enlarges it causes As the tumor enlarges it causes compressioncompression symptoms such as constipation, urinary freq, symptoms such as constipation, urinary freq, pelvic pressure, etc. pelvic pressure, etc.

- The tumour itself may undergo The tumour itself may undergo complicationscomplications of of torsion, rupture, haemorrhage, etc. torsion, rupture, haemorrhage, etc.

- Although Although weightweight loss is occasionally seen loss is occasionally seen withwith anorexia & intestinal obstruction, weight anorexia & intestinal obstruction, weight GAINGAIN is is much more common! much more common!

- Pelviabdominal Pelviabdominal massmass in most patients Benign in most patients Benign masses tend to be unilateral, cystic, mobile & masses tend to be unilateral, cystic, mobile & smooth, while a malignant mass tends to be smooth, while a malignant mass tends to be solid, nodular & immobile. A huge mass is often solid, nodular & immobile. A huge mass is often benign or of low-grade malignancy Ascites benign or of low-grade malignancy Ascites suggests malignancy or Meigsuggests malignancy or Meig’’s syndr. s syndr.

- Amenorrhoea is much more likely to occur - Amenorrhoea is much more likely to occur with functioning tumours. with functioning tumours.

-- Oestrogen- Oestrogen-producing tumours accounts for producing tumours accounts for 3% of all solid tumours of the ovary. Estro-3% of all solid tumours of the ovary. Estro-gen excess causes hyperplasia of the myo-gen excess causes hyperplasia of the myo-metrium (metrium ( enlarged uterus); hyperplasia of enlarged uterus); hyperplasia of the endometrium (the endometrium ( IUB or amenorrhea if the IUB or amenorrhea if the level of oestrogen does not fluctuate) level of oestrogen does not fluctuate) hyperplasia of the mammary gland tissue (hyperplasia of the mammary gland tissue ( enlarged tender breasts) & precocious enlarged tender breasts) & precocious puberty. 60% of puberty. 60% of estrogen-estrogen-producing producing tumorstumors occur in the childbearing period (occur in the childbearing period ( IUB); 30% IUB); 30% occur in postmenopausal women (occur in postmenopausal women ( postmenopausal bleeding) & 10% occur in postmenopausal bleeding) & 10% occur in children (children ( precocious puberty). In child-hood precocious puberty). In child-hood and early adulthood the tumours are mainly and early adulthood the tumours are mainly granulosa cells, and should be cons-idered as granulosa cells, and should be cons-idered as carcinoma In later life the tumors are usually carcinoma In later life the tumors are usually thecoma. In 14% of cases endo metrial thecoma. In 14% of cases endo metrial hyperplasia becomes atypical & car-cinoma hyperplasia becomes atypical & car-cinoma develops. develops.

- Androgen-producing tumours are - Androgen-producing tumours are of three types: Sertoli-Leydig cell of three types: Sertoli-Leydig cell tumour (arrhenoblastoma), hillar tumour (arrhenoblastoma), hillar cell tumour and lipoid cell tumour. cell tumour and lipoid cell tumour. Hillar cell tumourHillar cell tumour is very rare and is very rare and occurs in post-menopausal women. occurs in post-menopausal women. Defeminsation occurs followed by Defeminsation occurs followed by mild virilism... It is a small brown mild virilism... It is a small brown tumour in the ovarian hilum tumour in the ovarian hilum consisting of Leydig cells with consisting of Leydig cells with crystalloids of Reinkecrystalloids of Reinke

- It should be noted that non-functioning ovar-ian - It should be noted that non-functioning ovar-ian tumours may result in hormone production The tumours may result in hormone production The presence of tumour growth in the ovary presence of tumour growth in the ovary occasionally induces a thecal transformation of occasionally induces a thecal transformation of the ovarian stroma which in turn produces ste-the ovarian stroma which in turn produces ste-roids, sometimes androgenic but more commo roids, sometimes androgenic but more commo nly oestrogenic. This has been reported with nly oestrogenic. This has been reported with benign and malignant cysts, Brenner tumours, benign and malignant cysts, Brenner tumours, fibroma and secondary carcinoma of the ovaryfibroma and secondary carcinoma of the ovary

- Disordered small bowel motility secondary to - Disordered small bowel motility secondary to adhesions and interference with neural trans- adhesions and interference with neural trans- misssion through the mesenteric plexus is a misssion through the mesenteric plexus is a prominent feature and may simulate small-prominent feature and may simulate small-bowel obstruction. Colonic obstruction occurs bowel obstruction. Colonic obstruction occurs due to compression by the mass, less due to compression by the mass, less commonly due to invasion. commonly due to invasion.

Investigations Investigations CA 125:CA 125: 80% of patients with epithelial cancer 80% of patients with epithelial cancer has abnormal values (N: <35IU/ml). has abnormal values (N: <35IU/ml).

X-rayX-ray may distinguish a benign cystic teratoma may distinguish a benign cystic teratoma Psammoma bodies of serous tumors or ascites Psammoma bodies of serous tumors or ascites and dilated loops of intestine. and dilated loops of intestine.

CXR:CXR: Effusion or, rarely, metastases. Effusion or, rarely, metastases. IVU:IVU: Ureteric displacement obstruction or cystic Ureteric displacement obstruction or cystic

kidney. kidney. Barium enema (Barium enema ( sigmoidoscopy): sigmoidoscopy): Diverticulae Diverticulae

cancer colon, inflammatory bowel disease or cancer colon, inflammatory bowel disease or metastases. However, cystoscopy is not a metastases. However, cystoscopy is not a routine because involvement of bladder routine because involvement of bladder mucosa is exceedingly rare. mucosa is exceedingly rare.

Ultrasonography:Ultrasonography: Malignant tumor is generally Malignant tumor is generally multi loculated, more solid, >5 cm with thick multi loculated, more solid, >5 cm with thick septa & solid nodules Ascites is easily detect-septa & solid nodules Ascites is easily detect-able. able.

Differential diagnosisDifferential diagnosis

Ascites.Ascites.Retroperitoneal tumour. Retroperitoneal tumour. A functional cyst is suspected if uni-A functional cyst is suspected if uni-lateral & of a diameter <8-10 cm. lateral & of a diameter <8-10 cm. The likelihood of ovarian masses to The likelihood of ovarian masses to be malignant is 50% in the prepube be malignant is 50% in the prepube rtal and postmenopausal women; rtal and postmenopausal women; 10% in women of the reproductive 10% in women of the reproductive period. period.

ScreeningScreeningCA 125CA 125 is present in serum, semen, bronchial secre is present in serum, semen, bronchial secre tion, cervical mucus and amniotic fluid It is intensely tion, cervical mucus and amniotic fluid It is intensely expressed in >80% of epithelial ovarian cancers expressed in >80% of epithelial ovarian cancers (>65 (>65 IU/L)IU/L). It is used in: ovarian screening (detects only . It is used in: ovarian screening (detects only 50% of stage 1 disease); preoperative evaluation of 50% of stage 1 disease); preoperative evaluation of benign vs. malignant neoplasms; and follow-up of benign vs. malignant neoplasms; and follow-up of patients with ovarian cancer As a test for ovarian patients with ovarian cancer As a test for ovarian cancer, it has a sensitivity of 80% & a specificity of cancer, it has a sensitivity of 80% & a specificity of >95%. CA 125 is less likely to be raised in mucinous >95%. CA 125 is less likely to be raised in mucinous than in serous tumours. Other sources of increased than in serous tumours. Other sources of increased CA125 include active endometriosis, abdominal TB CA125 include active endometriosis, abdominal TB with ascites and tumours from the GIT Metastatic GI with ascites and tumours from the GIT Metastatic GI tumours can be differentiated from metastatic ovar-tumours can be differentiated from metastatic ovar-ian tumours by other investigations; serum SEA &/ or ian tumours by other investigations; serum SEA &/ or CA19-9 will be abnormal with the former but nor-mal CA19-9 will be abnormal with the former but nor-mal with the latter. with the latter.

Women with Women with 2 first-degree relatives with ovarian 2 first-degree relatives with ovarian cancer should have annual cancer should have annual recto-vaginalrecto-vaginal exam, CA exam, CA 125 evaluation and TVS from their mid 20s or when 125 evaluation and TVS from their mid 20s or when they are 5 years younger than the youngest affected they are 5 years younger than the youngest affected member of the family, whichever is sooner. member of the family, whichever is sooner. AFP:AFP: For teratomas. (N: <15ng/ml). For teratomas. (N: <15ng/ml).

Screening could save 3 y of life and is po Screening could save 3 y of life and is po tentially cost-effective. CA 125 + TVS tentially cost-effective. CA 125 + TVS +ve predictive value of 20%. 5 ope +ve predictive value of 20%. 5 ope rations for each cancer found are acce rations for each cancer found are acce ptable. Deaths in the screened group ptable. Deaths in the screened group = = ½½ that of the controls with that of the controls with significantsignificant improvement in survival (73mo vs 42) improvement in survival (73mo vs 42) However, no test(s) has proved prac-However, no test(s) has proved prac-tical! On the other hand, screening of tical! On the other hand, screening of women with +ve family history carries women with +ve family history carries a substantial risk of false +ve results. a substantial risk of false +ve results.

Prognosis:Prognosis: High mortality rate; >75% of High mortality rate; >75% of cases are diagnosed in stages III and cases are diagnosed in stages III and IV. Staging is the best indicator of IV. Staging is the best indicator of prognosis. 5-year survival rate for prognosis. 5-year survival rate for stage I = 90%. 5-year survival rate for stage I = 90%. 5-year survival rate for stage IV = <5%. stage IV = <5%.

In BRCA1 & BRCA2 +ve women, prophylactic bilat-In BRCA1 & BRCA2 +ve women, prophylactic bilat-eral SO reduces the rates of ovarian (up to 12%), eral SO reduces the rates of ovarian (up to 12%), tube & breast cancer. Individuals with a history of tube & breast cancer. Individuals with a history of hereditary ovarian or breast cancer should be advi-hereditary ovarian or breast cancer should be advi-sed to have sed to have prophylactic oophorectomyprophylactic oophorectomy once their once their family is completed or at the age of 35 (ovarian car-family is completed or at the age of 35 (ovarian car-cinoma is rare <45) However the risks of premature cinoma is rare <45) However the risks of premature menopause outweigh the benefits of a reduction in menopause outweigh the benefits of a reduction in in the risk of ovarian carcinoma. If only 1 relative is in the risk of ovarian carcinoma. If only 1 relative is affected, the advice is to have oophorectomy at affected, the advice is to have oophorectomy at hysterectomy indicated for other reasons. hysterectomy indicated for other reasons. Malignant tumours are Malignant tumours are stagedstaged surgically through a surgically through a vertical incision laparotomy Ascitic fluid or peritoneal vertical incision laparotomy Ascitic fluid or peritoneal saline washings & smears from the underside of the saline washings & smears from the underside of the diaphragm are collected before handling the t. Liver, diaphragm are collected before handling the t. Liver, subdiaphragm, bowel & mesenteries, omentum & subdiaphragm, bowel & mesenteries, omentum & aortic nodes are, then, inspected and palpated. aortic nodes are, then, inspected and palpated. Suspicious areas are biopsied Since 5% are meta-Suspicious areas are biopsied Since 5% are meta-static from the stomach & pancreas, these organs static from the stomach & pancreas, these organs must be carefully palpated. must be carefully palpated.

Management

This is followed by This is followed by removalremoval of as much malignant of as much malignant tissue as possible (surgical debulking or cytoreduc-tissue as possible (surgical debulking or cytoreduc-tive treatment). Masses need not be transected, tive treatment). Masses need not be transected, since peritoneal lines of cleavage are usually found. since peritoneal lines of cleavage are usually found. The following organs are removed in addition: the The following organs are removed in addition: the uterus, tubes, appendix & omentum. If cancer uterus, tubes, appendix & omentum. If cancer extends to the bladder & bowel, epithelial extends to the bladder & bowel, epithelial cancercancer tends to spread over, rather than penetrate these tends to spread over, rather than penetrate these organs, and a plane of cleavage can often be found. organs, and a plane of cleavage can often be found. Excision is facilitated by a retroperitoneal dissection Excision is facilitated by a retroperitoneal dissection along the iliac vessels and ureters from the pelvic along the iliac vessels and ureters from the pelvic brim to the lower limit of the tumor. This retropeiton brim to the lower limit of the tumor. This retropeiton eal access is very helpful and mostly safe, but it can eal access is very helpful and mostly safe, but it can lead to major vascular injury. The pelvic veins are lead to major vascular injury. The pelvic veins are especially vulnerable. especially vulnerable. This is followed by This is followed by chemotherapychemotherapy in advanced cases. in advanced cases. Taxanes + platinum = appropriate first choice. It Taxanes + platinum = appropriate first choice. It induces complete remission in 45% of patients with induces complete remission in 45% of patients with residual masses <2 cm; the percent is reduced to residual masses <2 cm; the percent is reduced to the half in larger masses. the half in larger masses. Second lookSecond look procedures can exclude recurrent procedures can exclude recurrent tumorstumors and thence allow discontinuing treatment with alky-and thence allow discontinuing treatment with alky-lating agents which frequently cause leukaemia. lating agents which frequently cause leukaemia.

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