Placental pathology

Placental pathology

1. PLACENTAL PATHOLOGY Moderator – Dr.Navya B.N Speaker – Dr.Ashwini K.T

2. PLACENTA Shape : Discoid Diameter : 15-20cm Weight : 450gm-600gm Thickness : 2- 2.5cm at its center and gradually tapers towards periphery Position : In the upper uterine segment (99.5%). Surfaces : Fetal surface and maternal surface .

3. Foetal Surface Smooth , glistening and is covered by the amnion which is reflected on the cord. The umblical cord is inserted near or at the center of this surface and its radiating branches can be seen beneath the amnion .

4. Maternal Surface Dull greyish red in colour and is divided into 15-20 cotyledons . Each cotyledon is formed of the branches of one main villus stem covered by decidua basalis .

5. Structure : Chorionic plate on fetal side Basal plate on maternal side Stem villi between the plates Intervillous space between stem villi filled with maternal blood .

6. Development Prelacunar stage : Blastocyst implantation :24 th day of menstrual cycle on upper posterior uterine wall . The embryonic pole of the blastocyst is attached to the endometrium . Syncytiotrophoblast (ST) proliferates towards decidua basalis & capsularis . Cytotrophoblast (CT) differentiates to primary mesoderm.

7. Early lacunar stage : Lacunar spaces from within ST around trabeculae (cords of ST) Lacunae enlarge and erode branches of uterine arteries & veins – uteroplacental circulation Primary lacunar stage : Trabeculae convert into primary villi with invasion by CT in central axis.

8. LACUNAR STAGE

9. Secondary villous stage : Primary mesodermal cells invade the primary villi . Tertiary villous stage : Fetal vessels derived from umbilical vessel appear within primary mesoderm . Numerous villi branch from tertiary villi in to intervillous space ( Labyrinthine structure )

10. Chorionic villi at embryonic pole proliferate rapidly to form chorion frondosum . Rest of the embryonic villi degenerate & disappear – chorion leave (CL). 3 RD month of pregnancy – decidua capsularis & parietalis fuse with regression of CL . Persistent chorionic frondosum + decidua basalis = HUMAN PLACENTA .

11. Primary villi – when trabeculae between lacunae of syncytiotrophoblast and intermediate trophoblast are invaded by cytotrophoblastic cells. Secondary villi – extraembryonic mesoderm invades primary villi which thus develops mesenchymal core. Tertiary villi – when the mesenchymal cores of villi gets vascularized .

12. TROPHOBLAST CELL TYPES Layer Location Description Cytotrophoblast Inner layer Single celled ,inner layer of the trophoblast forms syncytiotrophoblast villous IT and implantation site IT. syncytiotrophoblast Outer layer Thick layer of multinucleated syncytium that lacks cell boundaries and grows into the endometrial stroma secretes hCG . Intermediate trophoblast Implantation site , chorion , villi (dependent on subtype) Anchor placenta

13. FUNCTIONS OF: Villous intermediate trophoblast : - it maintains the structural integrity of the villi that anchor placenta to basal plate. Implantation site intermediate trophoblast – establishes the maternofetal circulation by invading the spiral arteries . Chorionic type intermediate trophoblast :- mechanical barrier to the maternal immune system.

14. FUNCTIONS OF PLACENTA 1.Respiratory function 2.Nutritive function 3.Excretory funcion 4.Production of enzymes 5.Production of pregnancy associated plasma proteins 6.Barrier function 7.Endocrine function

15. EXAMINATION OF PLACENTA Indications for Comprehensive Gross and Microscopic Examination by a Pathologist Maternal conditions Diabetes mellitus (or glucose intolerance) Hypertension (pregnancy-induced) Prematurity (pregnancy <32 weeks) Postmaturity (pregnancy >42 weeks) Maternal history of reproductive failure (defined as one or more previous stillbirths, spontaneous abortions, or premature births) Oligohydramnios Fever Infection Maternal history of substance abuse Repetitive bleeding (other than minor spotting of the first trimester) Abruptio placentae

16. Fetal and neonatal conditions Stillbirth or perinatal death Multiple birth Congenital abnormalities Fetal growth retardation Prematurity (<32 weeks) Hydrops Viscid/thick meconium Admission to a neonatal intensive care unit Severe central nervous system depression ( Apgar score of <3 at 5 minutes) Neurologic problems, including seizures Suspected infection Placental conditions Any gross abnormality of the placenta, its membranes, or the umbilical cord

17. STORAGE & PROCESSING Placentas should never be frozen. Freezing distorts the villi , obscures meconium , and compromises diagnosis. For fixation, the specimen should be placed in at least 10 times its volume of formalin. If samples are taken fresh for fixation before trimming, they should be no more than 2 cm thick.

18. Examination of placenta in ABORTION 1 ST TRIMESTER – MOST COMMON CAUSES : chromosomal abnormalities &“TORCH” infections Other causes – mechanical disturbances ,endocrine diseases. Grossly: Gestational sac – intact or ruptured Fetal parts Viable chorionic villi

19. MICROSCOPY: Fetal parts ,Chorionic villi or trophoblast – main criteria Enlarged hyalinized spiral artery & fibrinoid matrix – suggestive of intrauterine implantation. Other endometrial patterns strongly suggestive of gestation : gestational hyperplasia and Arias stella reaction .

20. SEPTIC ABORTION – Most common organisms- coliform & streptococci Diagnosis – is made by identifying the organism. HYDROPIC ABORTUS : villous swelling and cistern formation is absent . Villi are surrounded by attenuated trophoblast .

21. 2 nd TRIMESTER : Can be spontaneous ,surgically induced or prostaglandin induced Degenerative changes – focal decidual necrosis , intradecidual hemorrhage ,congestion & thrombosis of maternal vessels.

22. ANOMALIES OR NON NEOPLASTIC LESIONS

23. TWIN PREGNANCY Monochorionic placenta: indicative of monozygotic twins .Stripping of amnion reveals a continuous chorionic plate beneath the septum and vascular anastomoses between the twins.

24. Dichorionic placenta – compatible with either monozygotic or dizygotic twinning.rough chorionic ridge at the base of the septum and lack vascular anastomoses .

25. PLACENTA BILOBATA The placenta is separated into lobes Division is incomplete and vessels of fetal origin extend from one lobe to the other before uniting to form the umbilical cord .

26. SUCCENTURIATE LOBES Small accessory lobe ≥1,develop in the membranes at a distant from the periphery of main placenta , to which they usually have vascular connections of fetal origin Incidence :5% Retained in uterus after delivery and may cause serious hemorrhage Accompaning vasa previa – dangerous fetal hemorrhage.

27. PLACENTA MEMBRANACEA All of the fetal membrane are covered by functioning villi and the placental develops as a thin membranous structure occupying the entire peiphery of the chorion .

28. Circummarginate placenta - a flattened edge with a ridge of fibrin demarking the edge of the vascular plate. It often only involves a portion of the circumference. Circumvallate placenta - a peripheral cuplike insertion of the membranes at the placental surface.

29. Fenestrated Placenta : Central portion of a discoidal placenta is missing The defect involves only villous tissue with the chorionic plate

30. 1.Placenta accreta : placenta villi adhere to myometrium without an intervening layer of decidua . A. Placenta increta : villi within the myometrium usually involving previous cesarean section. B.Placenta percreta : villi penetrate through the uterine wall to the serosa .

31. PLACENTA ACCERTA

32. AMNION NODOSUM Small nodules <1mm on the extraplacental membrane – pathognomic of oligohydramnios .

33. PLACENTAL INFLAMMATION SUBCHORIONIC CYST : “UNDER THE FETAL PLATE” Origin from trophoblastic X cells Associated with diabetes mellitus or maternal fetal Rh incompatibility.

34. NECROTIZING VILLITIS FROM LISTERIA INFECTION

35. ACUTE INTERVILLOSITIS CHRONIC INTERVILLOSITIS

36. CHORIOAMNIONITIS Inflammation of the fetal membranes is usually manifestation of intrauterine infection. Associated with prolonged membrane rupture and long labor. Characteristic : clouding of the membranes Foul odor Definition : mono and polymorphonuclear leukocytes infiltrate the chorion Leucocytes are found in amnionic fluid ( amnionitis ) or the umbilical cord ( funisitis ). <20weeks almost all polymorphonuclear leukocytes : maternal origin. >20weeks: inflammatory response : maternal & fetal

37. Acute chorioamniontis

38. Intensive inflammatory infiltrate of the umblical cord ( Funisitis )

39. PLACENTAL INFARCTS most commom placental leisons Etiology : preeclamptic toxemia ,essential hypertension , Rh incompatibility and non toxic antepartum hemorrhage Types (by leison types) Located at the placental margin(90%),size <1cm (90%) Underneath the chorionic plate Intercotyledonary septa

40. PLACENTAL INFARCT 1.fresh infarct : dark red and firmer consistency. 2.old infarct : hard , white mass of granular appearance.

41. GHOSTS OF CHORIONIC VILLI IN A LONG STANDING PLACENTAL INFARCT Microscopic : 1.crowding of villi 2.virtual obliteration of intervillous space 3.marked congestion of villous vessels. 4. old infarcts : mass of crowded ghost villi are seen.

42. PLACENTAL SITE SUBINVOLUTION : SHOWING THICK WALLED VESSELS WHOSE LUMEN IS PARTIALLY OBLITERATED BY ORGANIZING THROMBI Curettage specimen : large maternal vessels from placental site partly filled with thrombi.

43. TUMORS and TUMOR LIKE CONDITIONS Chorioangioma ( Hemangioma ): Benign tumor of placenta Incidence : 1% Hamartomas of primitive chorionic mesenchyme . Diagnosis : Larger choriongiomas – sonographic findings Associated symptoms Small growths : asymptomatic Larger tumors : hydramnios or antepartum hemorrhage Complication : associated with low birth weight Fetal death and malformations are uncommon .

44. GROSS: Well circumscribed and purplish mass May protrude on fetal surface or may remain localized in the placental substance .

45. MICROSCOPY : composed of network of proliferating capillaries Mitosis may be present Degenerative changes are common

46. ASSOCIATIONS : Hydromnios Hemorrhage Premature delivery Premature placental seperation Placenta previa

47. CHORANGIOSIS: condition characterized by an increase in the number of vascular channels per villus . CHORANGIOMATOSIS : is as diffuse as chorangiosis but the vessels have thicker wall containing actin positive smooth muscle TERATOMAS of the placenta are very rare.

48. TUMOR METASTIC TO THE PLACENTA: Malignant tumors rarely metastasize to the placenta Melanoma , Leukemias and Lymphomas Tumor cells usually are confined within the intervillous space.

49. GESTATIONAL TROPHOBLASTIC DISEASE DEFINITION : is a spectrum of proliferation abnormalities of trophoblasts associated with pregnancy . 3 MAIN TYPES 1. HYDATIDIFORM MOLE 2.PLACENTAL SITE TROPHOBLASTIC TUMOR 3.CHORIOCARCINOMA

50. NIH classification of Gestational Trophoblastic Disease I . BENIGN GTD Complete hydatidiform mole Partial hydatidiform mole II . Malignant GTD Non metastatic GTD Metastatic TD 1.Good prognosis , low risk –absence of any risk factor 2.Poor prognosis ,high risk – presence of any risk factor a.Duration >4months b. Pretherapy level of beta hCG in serum >40,000mIU/ mL. c. Brain or liver metastasis d. GTD after term gestation e. Prior to failed therapy

51. GTN(modified WHO classification 1998) Non metastatic ( confined to uterus) Metastatic LOW RISK -< 4 months duration -initial serum HCG levels < 40,000miu/ml -metastasis limited to lungs and vagina -no prior chemotherapy -no preceding term delivery HIGH RISK - duration > 4 months -serum HCG levels > 40, 000 -brain or liver metastasis -failure of prior chemotherapy -Following term pregnancy -WHO score>7

52. HYDATIDIFORM MOLE The trophoblastic proliferation is associated with swelling of the villi Subdivided into complete partial invasive.

53. COMPLETE MOLE Caused by abnormal gametogenesis and fertilization . nuclei contains paternal chromosome Cytoplasmic DNA is maternal derived 46XX / 46XY Incidence : 1 in 2000 “Repetitive “ moles are usually complete mole Clinically : toxemia of pregnancy is seen (HTN ,edema , albuminuria ) , the affected uterus is disproportionately large for the stage of pregnancy, serum hCG levels raises even after 14 weeks.

54. GROSSLY : typically described as “ Bunch of grapes “ Villi showing hydropic degeneration No identifiable embryo ,cord , amniotic membrane.

55. MICROSCOPIC : Tophoblastic hyperplasia – characterstically has a circumferential but haphazard arrangement Vesicular swelling CISTERN formation

56. Immunohistochemically : hCG is widely distributed , PLAP is patchily distributed , both the alpha and beta inhibin are evident. Potential marker p57kip2 absent . P53 darkly stained in complete mole.

57. Treatment : initial curettage serum hCG levels at 10,20,30,45,and 60 days after the termination of molar gestation . If there is rising titre after 60 days chemotherapy is administered.

58. PARTIAL MOLE Associated with the presence of embryo. 69XXX or 69XXY and few show trisomy 16. GROSSLY : vesicular villi admixed with normal appearing ones .

59. MICROSCOPICALLY : focal edema leading to central CISTERN formation and stromal inclusions. Scalloping of villi . Trophoblastic proliferation. fibrosis of the villous stroma .

60. IMMUNOHISTOCHEMICALLY : localization of Hcg and hPL P57kip2 potential marker .

61. INVASIVE MOLE Refers to Nearly always of the complete type but occasionally of the partial type . villi penetrate deeply the myometrium and / or its blood vessels. myometrial penetration is extensive lead to persistent hemorrhage , serosa is intact. Vascular invasion as trophoblastic nodules outside the uterus such as vagina brain lung and spinal cord Distinguished from other moles by its invasiveness and the presence of villi which are also present in the metastatic foci.

62. GROSS MICROSCOPY

63. CHORIOCARCINOMA This is extremely malignant form of trophoblastic tumour may be considered a carcinoma of chorionic epithelium, although growth and metastasis behave like sarcoma . Characterized by abnormal trophoblastic hyperplasia and anaplasia , absence of chorionic villi

64. Incidence : 1: 250-5000 pregnancies in Asia and 1:4000 in the west. Origin: * Choriocarcinoma is a malignant tumour of the trophoblast . 1- About 50% of cases follow molar pregnancy. 2- 25% follow abortion 3- 23% follow normal pregnancy 4- 2% follow ectopic pregnancy. * In rare cases, the tumour arises as a teratoma in the ovary or testicle.

65. GROSSLY : The tumor arises in the endometrium as 1. Classically a soft,dark red, hemorrhagic,round nodular tumour with a marked tendency to form large pale areas of ischemic necrosis, foci of cystic softening . 2. Malignant tissue may be buried within the myometrium , inaccessible to the curette, or hidden in a distant metastasis. 3. However, any of these tumor patterns secretes ( hCG ) which causes cystic changes of the ovaries in about 30% of cases..

66. MICROSCOPICALLY : The classic pattern of choriocarcinoma has been described as “ BILAMINAR “, “DIMORPHIC, OR BIPHASIC “ . Tumor is composed of clusters of cytotrophoblast separated by streaming masses of syncytiotrophoblast leads to “Dimorphic plexiform pattern “. Villi are characteristically absent this differentiates Choriocarcinoma from invasive mole. Choriocarcinoma lacks the intrinsic endothelium-lined vascular channels in the centre of a tumour, making it a unique malignant solid tumour.

67. IMMUNOHISTOCHEMICALLY : positive for hCG and keratin Mode of spread: direct spread: to the parametrium , tubes and ovaries. Blood spread: occurs early to distant organs. The commonest sites are lungs (80%), vagina (30%), brain (10%) and liver (10%)

68. Diagnosis: A- symptoms: 1- Persistent or irregular vaginal bleeding: it is the commonest symptom occurring after labor, abortion or evacuation of a vesicular mole. Bleeding can occur within days or months but rarely after 2 years. 2- Vaginal discharge: which is blood stained and offensive due to ulceration and infection of the growth . 3- amenorrhea: may be present due to continuous hCG production. 4-Dyspnoea and haemoptysis are noticed with lung metastasis. 5-The appearance of neurological symptoms like hemiplegia , epilepsy, headache and visual disturbances suggest brain metastasis.

69. B- signs: (1) cachexia and severe anaemia . (2) fever may be present due to infection and necrosis (3) the uterus may be normal size or enlarged and soft. (4) the ovaries: may be enlarged and cystic. (5) metaststic nodules: in the vulva or vagina

70. C- investigations: (1) uterine curettage: should be done in every case of persistent or irregular uterine bleeding after labour , abortion or molar pregnancy. However, intramural tumour cannot be detected by curettage. (2) serum β- subunit of hCG : persistent or rising titres in absence of pregnancy are indicative of trophoblastic neoplasia . (3) biopsy: from metastatic vulvar or vaginal lesions.

71. (4) imaging: a- plain X-ray chest: may show secondaries in the form of " cannon balls" or "snowstorm" appearance. b- ultrasonography : to detect tumour , cystic ovaries and exclude remnants of conception. c- CT scan: for lungs, liver, brain and bone. (5) lumbar puncture: plasma hCG / CSF hCG ratio less than 60 strongly CNS involvement - metastases (6) blood studies: a- complete blood picture including platelet count b- Renal, liver and thyroid function tests c- Blood group

72. FIGO STAGING SYSTEM FOR GESTATIONAL TROPHOBLASTIC TUMOUR Stage I : Disease confined to uterus Stage II : GTT extending outside uterus but limited to genital str. ( adenexa vagina broad ligaments)

73. Stage III : GTT extending of lung with or without Known genital tract involvement Stage IV : All other metastatic sites

74. Managment Chemotherapy. Surgery. Radiation.

75. FOLLOW UP All patients with stage I through stage III disease should receive follow up with- Weekly measurement of HCG level until they are normal for 3 consecutive weeks. Monthly measurement of HCG value until level are normal for 12 consecutive months. Effective contraception during the entire interval of hormonal follow up.

76. WHO Prognostic Scoring System Score Prognostic factor 1 2 4 Age(years) ≤39 >39 — — Pregnancy history Hydatidiform mole Abortion, ectopic Term pregnancy — Interval (months) of treatment <4 4-6 7-12 >12 Initial hCG(mIU/ml) <10 3 10 3 -10 4 10 4 -10 5 >10 5 ABO Group O-A B-AB Largest tumor(cm) <3 3-5 >5 — Sites of metastasis Lung Spleen, kidney GI tract, liver Brain No. of metastasis — 1-4 4-8 8 Previous (treatment) — — Single drug 2 or more 0-4 low risk, 5-7 intermediate risk, >8 high risk for death

77. PROGNOSIS The cure rate is almost up to 100 percent in low risk and about 70 percent in high risk metastatic groups.

78. PLACENTAL SITE TROPHOBLASTIC TUMOR RARE form Also known as atypical choriocarcinoma and trophoblastic pseudotumor 75 % cases follow a normal pregnancy Paternally derived X chromosome may be necessary for its formation GROSSLY : well localized mass or ill defined

79. MICROSCOPICALLY : Large trophoblastic cells with abundant eosinophilic cytoplasm and nuclear pleomorphism invading the myometrium and vessel lumina

80. IMMUNOHISTOCHEMICALLY : hPL is strong , hCG is focal , positivity for keratin , CD66a , CD146,Pregnancy associated major basic protein , HLA-G Distinction with choriocarcinoma is made based on: Lack of a dimorphic population of cytotrophoblast and syncytiotrophoblast Lack of paucity of hemorrhage Presence of an interdigiting pattern of muscle invasion .

81. EPITHELIOID TROPHOBLASTIC TUMOR OCCURS IN REPRODUCTIVE AGE GROUP Primary tumor can be extra uterine and serum hCG LEVELS ARE elevated. GROSSLY : solid and cystic ,discrete and hemorrhagic

82. MICROSCOPICALLY : intermediate trophoblast forming nests and solid masses,necrosis is extensive. IMMUNOHISTOCHEMICALLY : diffuse reactivity for keratin , alpha inhibin , EMA , E – cadherin .

83. UMBILICAL CORD Length : 55 to 60 cm Diamter – 2cm Structure : consists of mesodermal connective tissue called wharton‘s jelly , covered by amnion . INSERTION : fetal surface of placenta near the center. “ eccentric insertion “ (70%) or at the center (30%).

84. CONTAINS : 1. One umbilical vein 2. Two umbilical artery 3. Remnants of the yolk sac and allontois 4. Wharton ‘s jelly

85. Marginal insertion

86. Velamentous insertion

87. Abnormalities of the length of the cord Long cord (> 90cm )is result of fetal activity . Umbilical true knot

88. Short cord <30cm delay in 2 nd stage labor Rupture CNS dysfunction Psychomotor impairments Congenital neuromuscular diseases.

89. SINGLE UMBILICAL ARTERY May be associated with other fetal congenital anomalies . Confirmed by microscopic examination .

90. CORD WITH OVERCOILING

91. FUNISITIS

92. REFERENCES 1.Mills SE , Carter D ,Sternberg diagnostic pathology , 4 th edition , Lipincott Williams and Wilkins. 2. Rosai J , Rosai and Ackerman Surgical pathology , 9 th edition , Elsevier. 3.Tavassoli F.A.,Devilee P( Eds ): World health organization classification of tumors .Pathology and genetics of tumors of the breast and female genital organs. IARC Press : Lyon 2003. 4.Dutta DC : Textbook of obstretics .7 th edition. 5.Internet sources.

93. THANK YOU