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Home , Foramen ovale (heart), Hydrops fetalis, Lymphangiogenesis

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Lymphology 48 (2015) 28-37

NEW ADVANCES ON PLACENTAL HYDROPS AND RELATED VILLOUS LYMPHATICS

L. Roncati, G. Barbolini, T. Pusiol, F. Piscioli, A. Maiorana

Department of Diagnostic and Clinical Medicine and of Public Health, Section of Pathology (LR,GB,AM), University of Modena and Reggio Emilia, Modena (MO), and Provincial Health Care Services (TP,FP), Santa Maria del Carmine Hospital, Rovereto (TN), Italy

ABSTRACT search for a more suitable therapy in case of mother’s hypertension during . Fetoplacental hydrops is the final stage of several pathological conditions in which the Keywords: placental hydrops, villous lym- and become edematous phatics, preeclampsia, vascular endothelium, and the develops an anasarcatic state podoplanin (D2-40), angiotensin-converting characterized by an excessive accumulation enzyme (ACE), Starling forces, of extravascular fluids in at least two serous cavities of the body. It is a common histo- The first literary description of placental logical finding of stillbirth, characterized by hydrops in a twin pregnancy dates back to the appearance of markedly edematous villi, 1609 by the work of Louise Bourgeois who suggesting an increased interstitial fluid regarded it as a of unknown etiology accumulation. The recent improved knowledge (1). In 1892 John William Ballantyne assumed of and the availability of its multifactorial etiology, suggesting that monoclonal selectively labeling ‘we are dealing not with a pathologic entity, lymphatic endothelium lead to the hypothesis but with a group of symptoms common to that villous is essentially a lymphedema several different morbid conditions’ (2). Only from defective lymphatic function following in 1946, after the identification of Rhesus inadequate villous blood circulation. Lymph- (Rh) factor, Edith Louise Potter distinguished edema is a morphologic phenotype found by immune hydrops from non-immune hydrops our research group in a 24-case series of (3). Fetoplacental hydrops is the final stage from different morbid conditions of several pathological conditions in which such as chromosomal aberrations, congenital the placenta and umbilical cord become malformations, inherited hemoglobinopathies, edematous (hydrops placentae) and the fetus and prolonged perinatal severe anoxia. Unlike develops an anasarca state characterized by long-lived organs, the placenta is devoid of an excessive accumulation of extravascular innervation by the autonomic nervous system; fluids in at least two serous cavities of the therefore, the vascular tone regulation and body (hydrops fetalis). It may be accompanied the peripheral perfusion are modulated by by gravidic maternal complications such as the expression of the angiotensin converting preeclampsia, , and , with enzyme (ACE) in the vascular endothelia. possible need for emergency cesarean section. This finding may suggest to the clinician to Grossly, a hydropic placenta, regardless of

Permission granted for single print for individual use. Reproduction not permitted without permission of Journal LYMPHOLOGY. 29 the trigger causes is soft, friable, and bulky, the incidence of immune hydrops in Rh+ weighing usually more than 1000 g, with a from Rh- mothers, the form most pale cutting surface. Sometimes in the hemo- frequently found in the past (6). lytic forms a jaundiced color of the umbilical cord and superficial chorionic vessels can be Etiology seen. On microscopy, the villi appear dilated with compression of the intravillous capil- Placental hydrops is classified into laries in which nucleated red blood cells immune and non-immune hydrops. Approxi- (NRBCs) can be detected. The villous stroma mately 75% of cases are non-immune based is edematous with an increase of the cytotro- (6). Immune hydrops, also known as erythro- phoblastic shell and of Hofbauer cells. blastosis fetalis or hemolytic disease of the fetus, is caused by the transfer through the Epidemiology fetoplacental compartment of maternal antibodies directed against surface antigens Placental hydrops has an incidence of (D, C, E, Fy, Kell, ABO) of fetal red blood about 11% with a high index of fetal, peri- cells as a result of alloimmunization (previous natal, and neonatal mortality (80%) as a pregnancy, amniocentesis, abdominal trauma), function of etiology, gestational age, severity, with a consequent intravascular hemolytic and therapeutic treatments performed (4). anemia (type II hypersensitivity reaction). It correlates with a low at The bone marrow compensates for this by and often intensive therapy for the neonate producing a high number of erythroblasts and is needed. The APGAR score was devised by by expanding into extramedullary sites, such in 1953 and it is based on five as spleen and liver, where marked deposits of tested parameters: Appearance (skin color), iron and consequent organ failure occur. The Pulse ( rate), Grimace (reflex irritability), high-output related to anemia Activity (muscle tone), and Respiration and hypoproteinemia from liver failure asso- (respiratory effort) each assigned a rating ciated with an oncotic pressure decreased are from 0 to 2. The maximum achievable score responsible for the development of hydrops. is 10 (5). It is checked immediately after In 1989, Geoffrey Machin advanced a delivery with the aim to evaluate the newborn further sub-classification of non-immune adaptation to extra-uterine life, in terms of hydrops according to the root causes updated vitality and efficiency of the primary as follows: cardiovascular abnormalities, functions. More in detail, the examination is infective conditions, hematologic disorders, performed at 1, 5 and 10 minutes of the genetic defects, intrathoracic lesions, infant’s life. Infants with score less than 4 nephro-intestinal , and neoplastic are in critical conditions and they require proliferations (7-10). immediate medical intervention in order to prevent longer-term neurological damage; Cardiovascular abnormalities those with a score between 4 and 6 are at risk for health in need of care, supervision, and Congestive heart failure resulting from retesting every 5 minutes; infants with score defects in electrical (tachyarrhythmias, between 7 and 10 are within a healthy normal atrioventricular blocks) or mechanical range. In the course of placental hydrops, (cardiomyopathies, premature closure of the is estimated to be more , septal faults, endocardial than 50%, reaching 100% if genetic defects fibroelastosis, valvular insufficiencies, are concomitant to it (4). hypoplastic left heart, cardiac tumors) The introduction of maternal prophylaxis systems is the major cause of non-immune with Rho globulins has successfully reduced fetoplacental hydrops.

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Infective conditions . The most widely used TTTS staging system was introduced by Quintero Intrauterine infections caused by viruses et al, and it is based on ultrasound findings (, Rubella, , (12). The TTTS Quintero staging system Herpes simplex, Hepatitis B, and Hepatitis includes five stages, ranging from mild C), bacteria (Treponema pallidum, Leptospira disease, with discordant amniotic fluid interrogans, Listeria monocytogenes) and volume, to severe disease, with demise of one protozoa (Toxoplasma gondii, Trypanosoma or both twins. More in particular, stage IV cruzi) can cause fetoplacental hydrops, refers to the presence of fetal hydrops as especially in mothers not previously exposed unfavorable prognostic factor (12). to the infective agent. Genetic defects Hematologic disorders Placental hydrops is found in fetuses Non-immune and related with storage syndromes such as Gaucher hematological disorders are responsible for and Niemann-Pick, or chromosomal defect placental hydrops due to high-output heart syndromes including Down (47, +21), failure with increased serum levels of lactic Edwards (47, +18), Patau (47, +13), and acid, aldosterone and atrial natriuretic pep- Turner (45, X0). In this last case, the tide, all factors regulating the intravascular incomplete formation of the lymphatic pressure according to the Starling’s model. drainage system into the thoracic duct leads The anemias from haemoglobinopathies are to the hydropic degeneration. those most commonly associated with hydrops; more in detail, homozygous -thalassemia is Intrathoracic lesions the leading cause (86%) of fetoplacental hydrops in Southeast Asia (7). A special The intrathoracic space-occupying mention is deserved to the twin-to-twin masses, associated with a mediastinal shift, transfusion syndrome (TTS). Superficial and reduce the venous return to the heart deep vascular anastomoses are constantly resulting in the formation of hydrops with present in all monochorionic twin ; central venous hypertension. Among these however, in 15% of cases a massive shift are: congenital cystic adenomatoid malfor- of blood from a twin (donor) to another mation (CCAM), chylothorax, diaphragmatic (recipient) can occur, resulting in anemia hernia, pulmonary sequestration, pleural and polycythemia, respectively. This collection, bronchogenic cyst, hamartoma condition is known by the term twin anemia- and mediastinal tumors. polycythemia sequence (TAPS). It is a possible finding during monochorionic Nephro-intestinal diseases diamniotic pregnancies, and it is defined as the occurrence of anemia in the donor and The congenital nephrotic syndromes polycythemia in the recipient, antenatally (autosomal recessive traits), in particular the diagnosed by middle cerebral artery (MCA) – Finnish type (CNF), are associated with peak systolic velocity (PSV) >1.5 multiples of fetoplacental hydrops for reduction of median in the donor and MCA PSV <1.0 intravascular oncotic pressure. A 10-fold multiples of median in the recipient, in the increase in the α-fetoprotein concentration in absence of oligohydramnios- polyhydramnios the amniotic fluid is suggestive for congenital (11). Hydrops may appear in both twins, due nephrotic syndrome. The diseases of the to high-output heart failure from anemia and gastrointestinal tract associated with hypo- circulatory-overload heart failure from proteinemia (volvulus, intussusception,

Permission granted for single print for individual use. Reproduction not permitted without permission of Journal LYMPHOLOGY. 31 perforation) are also associated with lymphoid origin including lymphangiomas fetoplacental hydrops, due to reduction of and lymphangiosarcomas (13). It has been intravascular oncotic pressure. demonstrated that anti-podoplanin reacts with lymphatic and not blood vascular Neoplastic proliferations endothelium (14). Moreover, in neoplastic tissues, this immunostaining has been able The voluminous neoplastic masses cause to clearly identify the lymphatic invasion fetoplacental hydrops due to high-output from primary cancers (15,16). CD31, also cardiac failure. Among these are , known by the acronym PECAM-1 (Platelet particularly in sacral localization, Endothelial Cell Adhesion Molecule), is a hemangiomas, rhabdomyomas, mesoblastic type 1 single-chain transmembrane protein nephromas, multiform glioblastomas, (135 KDa) belonging to the immunoglobulin medulloblastomas, and neuroblastomas, the superfamily which plays an important role last responsible for hydrops also in relation to in adhesive interactions between adjacent the secretion of vasoactive catecholaminergic endothelial cells, leukocytes, and platelets. substances. Moreover, the advanced-stage CD31 is expressed in all continuous endo- fetal neuroblastomas are often associated thelia, including those of arteries, arterioles, with maternal preeclampsia. The cavernous veins, venules, and capillaries (17). CD31 is lymphangioma (), which commonly used to demonstrate the presence usually occurs in the neck or underarm, is of endothelial cells in histological tissue commonly associated with a pronounced sections, favoring a correct interpretation of placental hydrops and therefore presumes the degree of tumor and related an abnormal placental development of the intravascular . Malignant endo- . thelial cells commonly retain the antigen, so CD31 immunohistochemistry is also a useful MATERIALS AND METHODS tool to identify the vascular origin of (18). CD143 is a type 1 single- Our research group has histologically chain transmembrane metallopeptidase (171 investigated a 24-case series of stillbirth from kDa) whose cofactor is zinc and belongs to different pathologic conditions, such as the family of carboxypeptidases. The enzyme chromosomal aberrations (4 cases), congenital catalyzes cleavage of decapeptide angiotensin malformations (8 cases), inherited hemoglobi- I into the octapeptide angiotensin II by nopathies (4 cases) and prolonged perinatal cutting the last two C-terminal aminoacids. severe anoxia (8 cases). The placental samples CD143 is expressed on endothelial cells, from stillbirths (12 male and 12 female) particularly those of pulmonary and renal were compared with 12 cases of full-term capillaries (19). The activation of macro- from live . All the samples phages and histiocytes induces the expression were fixed in 10% neutral buffered formalin of this molecule and its main targets are and then paraffin embedded. In addition to angiotensin I and bradykinin acting as a hematoxylin/eosin staining, immunohisto- blood pressure regulator. Angiotensin II is a chemistry for lymphatic endothelial cells potent hypertensive agent which controls (podoplanin), vascular endothelial cells arteriosus vasoconstriction and extravascular (CD31), and angiotensin-converting enzyme fluid balance through the renin-angiotensin- (ACE/CD143) was performed on both aldosterone system favoring water and pathological and healthy samples. Podoplanin sodium reabsorption. At the same time, ACE is a transmembrane O-linked sialoglycoprotein is able to degrade the vasodilator molecule (38 kDa) selectively expressed on lymphatic bradykinin, thus increasing the vasoconstrictor endothelium, as well as neoplasia of activity of angiotensin II (19).

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Fig. 1. A full-term placenta of healthy new-born delivered at 36th week. The staminal villous lymphatics (L) are brown-stained by the mouse monoclonal anti-podoplanin . The endothelia of arteriole (A), venule (V) and hematic capillaries (C) are unstained, because they do not express podoplanin. All the hematic vessels contain red blood cells (highlighted by yellow arrows). The lymphatics do not contain erythrocytes [Chromogen: DAB; original magnification: x100].

After deparaffinization, hydration, only one antibody (anti-CD143) and one endogenous peroxidase blocking, and heat- chromogen (DAB), while the second section induced antigen retrieval, tissue sections were was chronologically subjected to a double incubated for 30 minutes at room temperature staining in sequence, using two different with anti-podoplanin (clone D2-40 prediluted; antibodies (anti-podoplanin and anti-CD31) Dako, Glostrup, Denmark), anti-CD31 (clone and two different chromogens (new fuchsin JC70 prediluted; Ventana, Tucson, AZ, USA) and DAB), respectively. In the first step, this and anti-CD143 (clone 3C5 prediluted; Leica, procedure provided detection of any lymphatic Wetzlar, Germany). Biotinylated secondary structure using specific anti-podoplanin in antibody was applied and the staining product fuchsia color (new fuchsin). In the second detected with avidin-biotin complex (ABC) step, anti-CD31 antibody was used to identify against a hematoxylin counterstain. Detection the blood vascular structures in order to of the staining reaction was achieved by an avoid false lymphatic positives highlighted enzyme conjugated polymer complex adapted them in a brown color (DAB). for automatic stainers from Ventana Medical Systems. Moreover, for the first time, we RESULTS implemented an immunohistochemical development with double chromogen, that is In all the control cases of full-term 3-3’ diaminobenzidine tetrahydrochloride placentas from live births, thin-walled (DAB) and new fuchsin. For each case of lymphatics were clearly demonstrated, in stillbirth two sections for immunohisto- particular at the level of staminal villi by the chemistry were taken into consideration. employed anti-podoplanin antibody (Fig. 1). The first section was routinely stained with The staminal villus appeared to be composed

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Fig. 2. A placenta of stillborn at 14th week, affected by large retro-nuchal cystic lymphangioma and thymic hypoplasia, shows marked and diffuse villous stromal edema (A, hematoxylin/eosin). A number of dilated lymphatics, devoid of red blood cells within them, are fuchsia stained by anti-podoplanin antibody, while scattered squeezed capillaries are brown stained by the mouse monoclonal anti-CD31 antibody (B), a typical marker of hematic endothelia [Chromogens: new fuchsin and DAB, respectively; original magnification: x40]. of one arteriole, one venule, and several 24 cases of placental hydrops a 3+ score, hematic and lymphatic capillaries (Fig. 1). and therefore an ACE overexpression, was Lymphedema was a morphologic phenotype observed in hematic endothelia and Hofbauer constantly found by our research group in the cells, a placental type of histiocytes (Fig. 3). 24 cases of stillbirths from different pathologic In fact, as mentioned above (19), macrophages conditions, that is chromosomal aberrations and histiocytes can induce the enzyme (4 cases), congenital malformations (8 cases), expression. inherited hemoglobinopathies (4 cases), and prolonged perinatal severe anoxia (8 cases). DISCUSSION In all cases a number of dilated lymphatics was related to villous edema (Fig. 2A). The Immune and non-immune placental implementation of a double chromogenic hydrops are a common histological finding immunostaining, based on a close sequential of stillbirth, characterized by the appearance use of anti-podoplanin and anti-CD31, has of markedly edematous villi, suggesting an successfully allowed discernment of lymphatic increased interstitial fluid accumulation. It is from blood vessels. Moreover, it has also a well-known finding first reported as demonstrated compression of hematic capil- ‘presence of cavities and cisterns lined by laries by the adjacent hydropic lymphatics endothelioid cells’ (20). The recent improved (Fig. 2B). ACE expression was evaluated by a knowledge of lymphangiogenesis (21,22) and semi-quantitative method based on percentage availability of monoclonal antibodies for of endothelial cells which immunohisto- immunohistochemistry, selectively labeling chemically showed membranous positivity lymphatic endothelium (23,24), lead us to for anti-CD143 assigning the following hypothesize that villous edema is essentially scores: 0 score = 0%, 1+ score = 1-33%, 2+ a lymphedema from defective lymphatic score = 34-66% and 3+ score 67-100%. In function following inadequate blood villous control cases, scores ranged from 1+ (6 cases) circulation. Our immunohistochemical to 2+ (6 cases), while in all the aforementioned results support the presence of a lymphatic

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Fig. 3. A full-term placenta of healthy new-born delivered at 36th week (A): the capillaries of terminal villi and the arterial endothelium in a stem villus (insert, x100), filled with red blood cells, are brown-stained by the mouse monoclonal anti-CD143 antibody. A placenta of stillborn at 14th week, characterized by marked and diffuse hydrops (B): an ACE overexpression in hematic endothelia and in Hofbauer cells is observed by using the anti- CD143 antibody [Chromogen: DAB; original magnification: x40]. conductive network inside the placenta, as shallow trophoblast invasion and impaired suggested by Bellini et al (25), and agree with spiral artery remodeling (29-31). Moreover, those of Red-Horse (21), who succeeded in angiotensin II type 1 receptor agonistic detecting the presence of lymphatics in human autoantibody (AT1-AA) have been detected decidua by using a different marker, LYVE-1, in numerous preeclamptic women (32,33). a receptor specifically These data, together with the evidence of an localized to lymphatic endothelia. Further- increased incidence of pregnancy-induced more, Red-Horse et al (22) developed an in hypertension among mothers with pre- vivo experimental model of human placenta- existing cardiovascular diseases, support a tion, together with in vitro analyses, proving causal link between ACE activity and that placental cytotrophoblast stimulates preeclampsia (34). On the other hand, low lymphangiogenesis. The authors considered levels of ACE have been significantly corre- the placenta the trigger for the development lated with an increased risk for intrauterine of decidual lymphatic circulation and growth restriction (IUGR), , theorized its role in maintaining fluid balance and small birth weight (35, 36), confirming and maternal-fetal immune cell trafficking its functional importance in the adjustment during pregnancy (22). of maternal-fetal nutrient exchanges. The Unlike long-lived organs, the placental Ballantyne syndrome, also called ‘mirror hemolymphatic unit is devoid of innervation syndrome,’ is another gestational disorder by the autonomic nervous system; therefore, characterized by the association of maternal vascular tone regulation and the peripheral preeclampsia and fetoplacental hydrops, perfusion are modulated by ACE expression due to a variety of obstetric problems, in the vascular endothelia (26-28). High including immunohaematological and levels of ACE have been associated with metabolic diseases, fetal infections, and fetal preeclampsia, a gestational disorder malformations (37). Although the exact characterized by hypertension, proteinuria, etiopathogenetic mechanism of Ballantyne and utero-placental abnormalities, such as syndrome remains unknown, it can be

Permission granted for single print for individual use. Reproduction not permitted without permission of Journal LYMPHOLOGY. 35 curiously found in association with TTS varied placental vascular pathology frequently syndrome (38). observed in the second trimester of pregnancy. Moreover, our finding supports the The idiopathic forms of placental hydrops statement by Ito et al, according to whom the may be the result of a dysregulation in the feto-placental unit could induce ACE mRNA ACE-mediated system. The infarction events, expression in response to hypoxic conditions frequently found in the placenta, could (39), and agrees with the overview by also be caused by local impairments of this Kovalovszki et al, who have suggested that regulatory system. Moreover, it may be edema fluid is an interposed barrier to gas related to the clinical presentation of recur- exchange between mother and fetus (40). rent preeclamptic and eclamptic episodes According to the authors, capillaries can be complicating the pregnancy. It may also blocked by edematous swelling with a suggest to the clinician to search for a more subsequent reduction in blood flow through suitable therapy for the mother’s hyper- the villi. This abnormality, if widespread, tension during pregnancy. may reduce gas exchange and, therefore, they The placenta is a transient, multifunc- suggest that hypoxia could partly be prevented tional organ connecting two different humans by preventing the development of placental whose functioning is thus maintained by villous edema (40). In the literature, data combined hematic and lymphatic circulations. concerning the role of ACE in lymphologic In case of failure of both circulations, lymph- abnormalities are completely missing. From edema develops with cessation of maternal- our placental series, it emerges that ACE is fetal exchanges (barrier effect), a condition the intrinsic regulator of the placental incompatible with the life. The maintenance vascular system and, for this reason, it could of an adequate blood circulation through the have an indirect effect on surrounding villus, with related metabolic and trophic lymphatics, too. Its expression likely varies effects, is therefore essential to prevent forms depending on the intravascular pressure of hydropic hypoxia and to ensure deliveries status. Under basal conditions, in the event at term of healthy live births. of an increase of intravascular hydrostatic pressure or a decrease in the colloid-osmotic CONCLUSION pressure, ACE expression should fall in Our immunohistochemical results and endothelial and Hofbauer cells. On the other the etiological evaluation of placental hand, in the case of a decrease of hydrostatic hydrops permit focusing its pathogenesis on pressure or an increase in colloid-osmotic the delicate balance of peripheral vascular pressure, its expression should rise, following pressure, the so-called Starling forces (25). a negative feedback model. At the time when The peripheral pressure balance of the hydropic edema is established, there is a placenta can be affected by: compression of the capillaries resulting in a reduction of maternal-fetal exchanges and • INCREASE of hydrostatic venular ACE is overexpressed in the attempt to pressure from blood stasis, as it occurs in maintain the vascular intravillous perfusion the course of cardiovascular abnormali- perceived as inadequate to feed the fetus. If ties, genetic defects, intrathoracic lesions the pathological substrate, which causes and neoplastic proliferations; placental hydrops is not removed, a further • INCREASE of hydrostatic arteriolar accumulation of fluid in the extravascular pressure from peripheral vasodilatation, compartment with a subsequent increase of as it occurs in the course of hematologic edema is expected due to ACE overexpression disorders; (positive feedback model). A malfunctioning • DECREASE of intravascular oncotic hemolymphatic villous unit can explain the pressure from hypoproteinemia, as it

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