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Pediatric Pathology

Case 5 - Monochorionic Twin Placenta S/p Laser Coagulation of Intertwin Anastomoses for Twin-to-twin Transfusion Syndrome. No Residual Anastomoses Seen.

Monique De Paepe, Women & Infants Hospital, Providence, RI





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Clinical History
26-year-old primigravida presented at 14 weeks gestation with a twin pregnancy. Ultrasound examination revealed a single placental disc with a thin dividing membrane between two same-sex fetuses. Follow-up prenatal ultrasonograms between 15 and 17 weeks demonstrated appropriate and concordant fetal growth. At 19 weeks, the mother presented with breathing difficulties. Ultrasound revealed severe polyhydramnios of twin A, while twin B had no discernable amniotic fluid. Amnioreduction was performed (1,500 mL of amniotic fluid was removed from twin A). At 20 weeks gestation, polyhydramnios was again seen in twin A. Doppler ultrasound examination revealed reversed end-diastolic flow in the umbilical artery of twin B. Anhydramnios was still present, and the bladder could not be visualized. Twin A had a dilated right ventricle and grade I tricuspid regurgitation. A decision was made to proceed with fetoscopic laser ablation of the intertwin anastomoses. One day after the laser ablation procedure, twin A no longer had tricuspid regurgitation, although the heart remained subjectively dilated. A small bladder was seen in twin B, and Doppler ultrasound revealed intermittent absent end-diastolic flow in the umbilical artery. At 23 weeks gestation, dual fetal demise was diagnosed. Delivery was induced. The placenta weighed 325 g (between 75th and 90th percentile for a 23-week twin placenta). Gross images of the placenta are shown in Figures 1-4. The cord of twin B had a velamentous insertion and was avulsed (Fig. 1). Several suspected laser ablation sites were detected upon gross examination (Fig. 2). Vascular injection studies were performed to delineate the superficial chorionic vasculature (Fig. 3). No connections were noted between the two vascular beds, but several occluded vessels were seen crossing the equator between the two twin circulations (Fig. 4). Histologic sections of side A showed relatively large and focally edematous chorionic villi (Fig. 5), while side B showed small, hypoplastic villi (Fig. 6). Sections of the laser ablation sites revealed necrotic and thrombosed chorionic plate vessels (Fig. 7-8), focally associated with clusters of avascular villi (Fig. 9).


Case 5 - Figure 1
Case 5 - Figure 2
Case 5 - Figure 3

Case 5 - Figure 4
Case 5 - Figure 5
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Case 5 - Figure 7
Case 5 - Figure 8
Case 5 - Figure 9

Introduction
Approximately 20% of all twin pregnancies are monochorionic, and 9% to 15% of all monochorionic twin gestations are complicated by severe chronic twin-to-twin transfusion syndrome (TTTS), characterized by a gradual shift of blood volume from the donor twin to the recipient twin through placental vascular connections [1, 2, 3] . The prognosis of severe, untreated chronic TTTS diagnosed in mid-trimester fetuses is extremely poor, with mortality rates exceeding 70% [4] . Laser photocoagulation of the intertwin anastomoses is currently considered the optimal first-line therapy for severe TTTS diagnosed before 26 weeks of gestation. The pathologist's understanding of the pathophysiology of TTTS and of the TTTS-associated fetal and placental pathology, including the findings related to laser ablation of the anastomoses, can be of great benefit to the patient and the involved obstetrical/neonatal/surgical team.

Pathologic Findings
A monochorionic twin placenta is shown. The placental membranes, including the intertwin dividing membrane, have been removed. The cord of twin B (donor) has a velamentous insertion and is avulsed (Fig. 1). The cord diameter of twin B is smaller than that of twin A (recipient). Several suspected laser ablation sites are detected upon gross examination, recognizable as hemorrhagic vessels containing coagulated blood along the equator (Fig. 2). Vascular injection studies were performed to delineate the superficial chorionic vasculature (Fig. 3). The following color scheme was used: twin A: artery: green and vein: yellow; twin B: artery: red; vein: blue. No residual connections are noted between the two vascular beds, but several occluded vessels are seen crossing the equator between the two twin circulations (Fig. 4). Histologic sections of side A show relatively large and focally edematous chorionic villi (Fig. 5), while side B shows small, hypoplastic villi (Fig. 6). Sections of the laser ablation sites reveal necrotic and thrombosed chorionic plate vessels (Fig. 7-8), focally associated with clusters of avascular villi (Fig. 9).

Final Diagnosis
Monochorionic twin placenta s/p laser coagulation of intertwin anastomoses for twin-to-twin transfusion syndrome. No residual anastomoses seen.

Differential Diagnosis
In addition to chronic TTTS, less common forms of TTTS have been described. Acute perimortem TTTS occurs after intrauterine fetal demise of a co-twin and is caused by exsanguination from the surviving twin into the low-pressure circulation of the dying co-twin. Acute perinatal TTTS may occur during birth due to acute intertwin shifts of blood resulting from blood pressure differences associated with uterine contractions, changes in fetal position or delayed clamping of one of the umbilical cords at delivery. Twin anemia-polycythemia sequence (TAPS) is a recently described variant of TTTS characterized by the presence of a large intertwin difference in hemoglobin and reticulocyte levels without any sign of oligohydramnios-polyhydramnios sequence as seen in chronic TTTS (TOPS) [5] . TAPS may occur spontaneously or after laser surgery in the treatment of TTTS. Initial evidence suggests that TAPS placentas may have a unique angioarchitectural signature (unlike TTTS), characterized by the presence of only few and thin AV anastomoses, virtually always in the absence of AA anastomoses [6] .

Case Discussion

Diagnosis and staging of TTTS.
The diagnosis of TTTS relies upon strict ultrasound criteria of twin oligohydramnios-polyhydramnios sequence (TOPS). The main diagnostic criterion for severe TTTS is the presence of oligohydramnios (deepest vertical pool in amniotic sac ≤ 2 cm) in one twin and polyhydramnios (deepest vertical pool ≥ 8 cm before 20 weeks; between 21 and 26 weeks the cut-off is 8 cm in the United States and 10 cm in Europe [7] ) in the other twin, occurring in the setting of monochorionic placentation (single placental mass, thin intertwin membrane, similar external genitalia, and absence of a "twin peak" sign by ultrasonography). The oliguric twin is named the donor and the polyuric twin the recipient. In cases of severe oligohydramnios, the donor twin may be referred to as the "stuck twin", since this fetus appears wrapped in the membranes and plastered against the placental surface. Secondary to the underlying hypervolemia and its cardiac effects, the recipient twin may exhibit a wide spectrum of echocardiographic findings, encompassed under the term TTTS-related cardiomyopathy [8, 9, 10] .

Once the diagnosis of TTTS is suspected, a detailed ultrasound assessment is made, including Doppler studies of both twins, to allow staging of the disease. The most widely used classification is the ultrasound-based Quintero staging system [11] , although its prognostic value is debated [12, 13] . Fetal echocardiography may be added to the initial assessment to evaluate cardiac function in the recipient twin [10] .

Table 1. Quintero staging system for severe TTTS

Stage Ultrasonographic findings
I Polyhydramnios around recipient (deepest vertical pocket = 8 cm)
Oligohydramnios around donor (deepest vertical pocket = 2 cm)
Bladder of donor twin visible. No abnormal Doppler studies.
II As stage I, plus bladder of donor twin not visible.
No critically abnormal Doppler studies
III As stage I, plus = 1 critically abnormal Doppler studies present
  • Absent or reversed end-diastolic flow in umbilical artery (donor and/or recipient)
  • Pulsatile flow in the umbilical vein (usually recipient)
  • Reverse flow in the ductus venosus (usually recipient)
IV As stage I, plus evidence of hydrops in one or both twins; hydrops defined as abnormal fluid accumulation in = 2 compartments
  • Abdomen (ascites)
  • Thorax (pleural or pericardial effusion)
  • Subcutaneous tissues (skin edema or increased nuchal fold)
  • (Amniotic space/polyhydramnios)
V (Impending) demise of one or both twins (rarely used)
Adapted from Quintero et al. [11]

It is important to note that the diagnosis of TTTS is based solely on ultrasound criteria. The diagnostic value of traditionally accepted neonatal criteria including discordant hemoglobin levels (hemoglobin difference > 5 g/dL) and discordant weight (weight difference > 20%) has been challenged [14] .

Pathophysiology of TTTS.
The pathogenesis of TTTS remains incompletely understood. The condition is complex, dynamic and multifactorial with both placental and fetal (and likely maternal) components. Increased risk for development of TTTS in diamniotic-monochorionic twin gestations has been linked to a number of anatomic placental variables, including uneven sharing of the single-disc placenta, velamentous or marginal cord insertion, the presence of deep intertwin artery-to-vein anastomoses, and the absence of superficial artery-to-artery anastomoses [15, 16, 17, 18, 20] .

In view of its putative critical role in the pathogenesis of TTTS, the architecture of the intertwin vascular communications has been the subject of numerous studies [17, 18, 20, 21, 22] . Placental vascular communications occur in virtually all monochorionic placentas [20, 22, 23] and are either superficial (lying on the surface of the chorionic plate) or deep (within the placental parenchyma). Artery-to-artery (AA) and vein-to-vein (VV) anastomoses are direct and superficial intertwin connections. In contrast, artery-to-vein (AV) anastomoses are deep and refer to a shared cotyledon with arterial supply from one twin and venous drainage to the other [21] . Unlike the superficial AA and VV anastomoses, AV anastomoses are obligatorily unidirectional; AV imbalance directed from donor to recipient is traditionally believed to be a critical factor in the uncompensated blood flow from one twin to the other [24] .

The presence of AV anastomoses without a compensating AA anastomosis is associated with a higher risk for the development of TTTS [20, 22] , which has led to the widely accepted belief that AA anastomoses have a protective role in monochorionic pregnancies, presumably by equilibrating intertwin hemodynamic imbalances created by uneven flow through AV anastomoses [25] .

The imbalance of blood volume brought about by the presence of intertwin AV anastomoses is believed to initiate a cascade of (mal)adaptive events in both fetuses that, paradoxically, lead to significant morbidity and mortality in untreated TTTS twins. Mediators of these secondary effects include atrial natriuretic peptide [26] , brain natriuretic peptide [27] , antidiuretic hormone, effectors of the RAS system [28, 29] and endothelin-1 (increased) [27, 30] . Although their exact mechanisms of action remain incompletely understood, these various hormonal and related mediators have been implicated in the cardiovascular anomalies observed in recipient twins.

Both fetuses are at risk for dying; in 66% of cases demise of the donor occurs first [31] . Because of the existing feto-fetal shunts, the sudden drop in arterial perfusion pressure in the dying twin results in a "twin reversed arterial perfusion" sequence and a steal phenomenon from surviving to dying twin [32] . Death of the co-twin often follows death of the first twin within hours; surviving twins have a 25% to 30% risk of severe neurologic or cardiac anomalies [33] .

Management of TTTS: Fetoscopic laser coagulation of intertwin anastomoses.
Since the randomized Eurofoetus trial demonstrated higher survival rates after laser therapy (76% survival of at least one twin) compared with serial amnioreduction (56% survival), endoscopic laser ablation of anastomotic vessels is at present considered the treatment of choice for severe TTTS diagnosed before 26 weeks of gestation [34] . Fetoscopic laser coagulation, first described by De Lia et al. in 1990 [35] , uses a laser beam to photocoagulate the intertwin vascular communications that underlie the pathogenesis of the syndrome. The rationale for this technique is to interrupt the hemodynamic imbalance that defines the syndrome by 'dichorionizing' an initially monochorionic placenta. This will also prevent further shifting of blood volume between twins and ensure functional separation of the two circulations in case of subsequent fetal demise [36] .

Non-specific therapeutic options for TTTS include expectant management, repetitive amnioreduction of the polyhydramniotic sac (amniodrainage), amniotic septostomy (puncture of the intertwin septum to – temporarily – equilibrate amniotic fluid volume), elective preterm delivery, selective reduction of one fetus, or termination of the pregnancy [37] .

Placental pathology of TTTS: Gross examination.
Placentas of TTTS pregnancies have significantly higher frequencies of velamentous or marginal cord insertion (usually of the donor twin), uneven placental sharing (the donor usually having the smaller placental share), absence of AA anastomoses and presence of VV anastomoses compared with non-TTTS placentas [15, 16, 17, 18, 19, 20] . Deep AV anastomoses are equally prevalent (≥ 95%) in TTTS and non-TTTS placentas. Similarly, the total and net numbers (number in one direction minus number in other direction) of AV anastomoses are similar in both groups [20] .

Based on these data, the pathologist examining a diamniotic-monochorionic twin placenta needs to focus on recording those placental variables that are known to be associated with an increased risk for TTTS. Such relevant placental characteristics in the context of TTTS include the types of cord insertion (paracentral, eccentric, marginal or velamentous); the degree of placental sharing (based on location of the vascular equator) and the presence or absence of superficial AA and VV anastomoses. In the vast majority of cases, these key placental features can readily be assessed by routine gross examination of the non-injected twin placenta.

Placental pathology of TTTS: Analysis of the choriovascular anastomoses.
The pathologist may be requested to provide an accurate and detailed assessment of the vascular anastomoses in monochorionic twin placentas. Vascular injection of monochorionic twin placentas may be indicated under selected circumstances, including: in all laser-ablated placentas, in the absence of grossly identifiable AA anastomoses (see below), in monochorionic twin pregnancies with atypical course, for research purposes, and whenever requested by clinicians or patients.

While large-sized superficial AA and VV anastomoses may be readily identified by routine gross examination of the placenta, accurate delineation and categorization of smaller-sized vessels, and in particular of complex AV anastomoses, requires careful injection studies. Several vascular injection methods have been described that use milk, water, barium, colloid, resin, alcohol-resistant dyes or plastics. We have previously described in detail a practical dye-based vascular injection technique that can be applied in a routine surgical pathology setting [21] .

In classifying the various types of anastomoses, it is important to remember that arteries can be identified by their tendency to cross over accompanying veins. The AA and VV anastomoses are superficial, and directly cross from one cord to the opposite cord without entering the chorionic plate. Deep AV anastomoses, in contrast, are indirect and characterized by penetration of unpaired, contralateral arteries and veins into the chorionic plate within close proximity to each other [21] .

Relevant feedback upon examination of the post-ablation placenta includes the localization of foci of laser impact with respect to vascular structures, the type and number of coagulated vessels, and the characterization of any residual anastomoses [38] . We recently reported our experience with placental examination following selective laser ablation in TTTS [38] . Foci of laser impact were identifiable in all placentas examined within one month after laser coagulation. Located along the recipient side of the dividing membrane, the laser-treated vessels appeared hemorrhagic and showed an abrupt interruption of dye filling. In placentas examined more than one month after intervention, the most frequent finding was the absence or relative paucity of intertwin anastomoses, associated with subchorionic fibrin deposition. Microscopically, laser-treated vessels showed varying degrees of necrosis, associated with focal hemorrhage, avascular villi and fibrin deposition in the underlying parenchyma [38] .

Most authors agree that, even with optimal surgical technique, some patent twin-twin anastomoses may remain present after laser ablation. The prevalence of residual anastomoses varies widely in the literature (5% to 32% [39, 40, 41] ), and may depend not only on the diligence of the ablation, but on the assiduity of the pathologist in finding every last twin-twin connection, as well. The presence of residual anastomoses following laser surgery may be a source of post-ablation complications. Depending on their number, size, direction and type, residual intertwin anastomoses can result in persistent TTTS, reversal of TTTS [42, 43, 44] , twin anemia-polycythemia sequence (TAPS, see below), intrauterine demise of one or both twins, or hypotensive sequelae in the surviving twin [45] . Most residual surface anastomoses are small (< 1 mm in diameter) and located near the placental margin [46] . Deeper intertwin anastomoses below the chorionic plate that cannot be visualized by routine examination and cannot be photocoagulated by laser therapy have been described [39] but are believed to have limited hematological or hemodynamic significance [47] .

In the absence of a compensating AA anastomosis, imbalance of AV anastomoses is associated with an increased risk for TTTS [20] . This choriovascular pattern is seen in only 14% of TTTS placentas but has 99% specificity as post-hoc predictor of TTTS [20] . For this reason, absence of identifiable AA anastomoses by gross examination may represent another indication for vascular injection, when clinically warranted.

Conclusions.
  • The diagnosis of TTTS is based on prenatal ultrasonographic evidence of oligohydramnios/polyhydramnios.

  • TTTS does not have a unique placental or choriovascular signature. However, placentas of TTTS pregnancies have significantly higher frequencies of velamentous or marginal cord insertion, uneven placental sharing, absence of AA anastomoses and presence of VV anastomoses compared with non-TTTS placentas. This may warrant the routine inclusion of these four placental descriptors in the pathology report. These findings are usually evident by gross examination of the non-injected placenta.

  • Detailed description of the chorionic angioarchitecture following vascular injection may be reserved for selected indications; such as the follow-up of placentas treated with laser photocoagulation of intertwin anastomoses for TTTS.

  • Interpretation of the vascular injection studies is based on the following anatomic characteristics of the placental choriovasculature:
    • Chorionic arteries course superficial to accompanying veins

    • Intertwin AA and VV anastomoses are superficial and direct

    • Intertwin AV anastomoses are "deep" and indirect
  • It is important for pathologists to understand the strengths and limitations of placental examination and analysis of the choriovascular anatomy in monochorionic twin gestations.

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  47. van den Wijngaard JP, Lopriore E, van der Salm SM, Schaap AH, Vandenbussche FP, Deruiter MC, van Gemert MJ: Deep-hidden anastomoses in monochorionic twin placentae are harmless. Prenat Diagn 2007, 27:233-239