Of the 23 patients of the cases group, 23 had breast ductal infiltrating carcinoma. Nineteen of 23 cases had a poorly differentiated (G3) cancer.
Clinical characteristics of the cases are detailed in Table 1.
All patients were treated with 2-6 cycles of chemotherapy starting after 16 weeks of gestation. The combination of every three weeks Epirubicin (75 mg/sqm) and Cyclophosphamide (750 mg/sqm) was used in 12 patients, while weekly Epirubicin (35 mg/sqm) was used in 11 patients.
Possible complications were studied during pregnancy, delivery and till discharge of all patients.
None hypertensive disorders during pregnancy complications were reported in patients treated with chemotherapy during chemotherapy administrations. In particular no pre-eclampsia episodes were observed.
Birth weight was consistent with gestational age in all babies in both groups. Median gestational age at delivery was 36 weeks (range 34-38 weeks) for cases and 39 weeks (range 36-40 weeks) for controls.
No babies had uneventful outcomes and no perinatal mortality or fetal malformations were observed.
Clinical characteristics of the cases are detailed in Table 1.
We classified histological lesions according to the Amsterdam Placental Workshop Group Consensus Statement  in maternal vascular malperfusion of the placental bed, fetal vascular malperfusion and delayed villous maturation.
Maternal vascular malperfusion of the placental bed
Accelerated villous maturation – Twenty out of 23 cases (86%) showed hypoxia-induced villous alterations, including increased syncytial knotting (Tenney-Parker changes), perivillar fibrin deposits, distal villous hypoplasia or accelerated maturation and focal villous chorangiosis (Figure 1). These alterations were found in 19 out of 23 controls (83%), with no statistically significant difference between the two groups.
All cases showed a certain degree of villous agglutination, characterized by a mixture of extracellular matrix and fibrin that completely surrounds large zones of distal villi with preservation of the intervillous space.
In association, we found in 8/23 cases (34%) intravillar fibrin deposition and 8/23 cases (34%) developed intravillar calcifications; these findings were not reported in controls, with a statistically significant difference between the two grouos (p=0.006). In addition, 14/23 cases (60%) and 17/23 controls (28%) showed perivillar calcification (p=n.s.).
Peculiar histological characteristics of this category are illustrated in Figure 2 and 3.
Fifteen out of 23 cases (65%) and 8/23 controls (35%) showed foci of villous immaturity, which is characterized by villi small for the gestational age with edematous stroma (p=n.s.).
Distal villous hypoplasia – In all cases and in 19/23 controls (83%) we observed a marked variation in villous diameters with formation of adherent villous clusters, distal villous hypoplasia and peripheral villous hypoplasia (Figure 4) (p=n.s.). The villous tree showed a decrease in the rate of distal to proximal stem villi. Clusters of syncytial cells surrounded knots of long, thin and non-branching immature intermediate villi. There was a decreased number of fetal arterioles and those remaining showed hypertrophy of the media.
Distal villous immaturity was seen in association with distal villous hypoplasia and it was characterized by an increased number of enlarged distal villi, stromal cells and villous macrophages. Capillaries tended to be central with a decrease in vasculosyncytial cells.
Fetal vascular malperfusion
Stem vessel obliteration - All cases and 19/23 controls (83%) showed partial or complete stenosis associated with hypertrophy and fibrosis of the arterial wall of truncal vessels of first, second and third order with evidences of thrombosis and recanalization of these vessels in few cases (p=n.s.). Consequently, we observed fibrotic and avascular villi intermixed with normally developed villi (see later).
Thrombosis - Two out of 23 cases (8%) and none of the controls showed fibrin deposits and lysed red blood cells arranged in parallel layers to chorial plaque (p=n.s.).
One out of the 23 cases (4%) and none of the controls showed thrombosis that pushed villi to the periphery of the parenchyma; villi showed a laminated appearance and were sometimes fibrotic (p=n.s.).
Intervillous thrombi mainly occurred in the intervillous space in central areas of the placenta. Thrombi appeared first as fresh red clots, which then became laminated thrombi and finally old white lesions, with no real organization. Intervillous thrombi contained both fetal and maternal red blood cells.
Two out of 23 cases (8%) showed subchorial thrombosis and all cases marked thickening of the decidual and spiral arteries wall.
Avascular villi – Two or more small foci with total loss of terminal villi capillaries in association with villar fibrosis were found in all cases.
Delayed villous maturation
The presence of marked acute and chronic infiltrate between villi (intervillositis) was found focally in 1 out of 23 cases (4%) and in 2/23 (8%) of the controls (p=n.s.).
Acute intervillositis was characterized by the presence of neutrophils in the intervillous space with occasional involvement of contiguous villi, often accompanied by patchy intervillous fibrin. On the contrary, chronic intervillositis showed a predominance of intervillous macrophages.
A chronic villous inflammation not associated with recognizable microorganisms (non-specific villitis) was identified in the villous connectival axis in 1 out of 23 patients (4%) but in none of the controls (p=.n.s.).
Microscopically, lymphocytes were mixed with normal villi, accompanied by fibrin deposition and villous agglutination.
Finally, 3 out of 23 cases (13%) and 2/23 controls (8%) showed acute choramniositis and 1 out of 23 cases (4%) and none of the controls acute funisitis (p=.n.s.).
One specimen displayed a parenchymal chorioangioma, characterized by abundant fibrous connective tissue associated with small, congested vascular structures surrounded by proliferative mono stratified endothelium.
As no major fetal abnormalities were present at birth, a correlation between histological alterations and fetal outcome could not be made.
No statistically significant correlation with placental macroscopic findings such as placental weight between cancer and control group was found.