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Pediatric Pathology
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Case 2 -
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Transient Abnormal Myelopoiesis of Down Syndrome, Manifest as Fetal Thrombotic Vasculopathy (Multiple Chorionic Plate and Stem Villous Vessel Thrombi)
Amy Heerema McKenney, Stanford University, Stanford, CA
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Clinical History
A 43 year old G8P5025 presented at 32 and 1/7 weeks gestation with vaginal bleeding and preterm labor. A 2nd trimester fetal ultrasound had demonstrated duodenal atresia, pelviectasis and polyhydramnios. The patient declined amniocentesis. She delivered with clinical concern for placental abruption and the placenta was submitted to pathology for examination.
Pertinent Laboratory Data:
The trimmed placental disc weight was 370 grams. The umbilical cord measured 10 cm in length by 1.4 cm in diameter. It inserted eccentrically, contained three vessels, demonstrated normal coiling and had no knots or other gross lesions. The membranes inserted normally at the disc margin. The chorionic plate vasculature showed normal dispersion, and demonstrated no calcifications. The maternal surface demonstrated an adherent clot, consistent with the delivery observations of retroplacental hemorrhage. The parenchyma showed compression deep to the retroplacental hemorrhage, but no other lesions. Microscopic examination showed large vessel fetal thrombotic vasculopathy with unusually cellular thrombi.
Introduction:
The early thrombi seen in the chorionic plate and stem villous vasculature of this case are an
uncommon finding. Approximately 2% of placentas submitted for pathologic examination at Stanford have
multiple large vessel thrombi or umbilical thrombi. These are large vessel manifestations of fetal
thrombotic vasculopathy (FTV). The unusual cellularity of the thrombi in this case led to further
immunohistochemical investigations not commonly warranted in FTV.
Pathological/Microscopic Findings and any Immunohistochemical or Other Studies:
The thrombi include a mixed cellularity of normoblasts, left-shifted myeloids, and occasional small
mature megakaryocytes. An excessive number of immature appearing cells with high nuclear to cytoplasmic
ratios and nucleoli are concerning for blasts. Immunostains show that the cells are negative for CD34,
Glycophorin, and myeloperoxidase. They express LAT ("linker for activated T-cells", a marker of
megakaryocytes and T-cells), but not CD3.
Differential Diagnoses:
While the artifact of settled or "layered" blood may appear very cellular in the fetal circulation,
the cells present are typically mature peripheral blood components. Increased hematopoietic progenitors
in the fetal circulation may reflect erythroblastosis, a leukemoid reaction in a stressed fetus,
transient abnormal myelopoiesis of Down syndrome, or congenital acute leukemia. Placental dissemination
of a congenital small round blue cell tumor (most commonly neuroblastoma) can have a similar appearance.
In this case, the number of blast-appearing cells was too excessive for a leukemoid reaction or fetal
erythroblastosis, both of which tend to show a predominance of normoblasts with fewer numbers of
proerythroblasts. The lack of glycophorin reactivity in the primitive cells confirms that they are not
proerythroblasts. The presence of small megakaryocytes in the fetal circulation can be seen in leukemoid
reactions, but usually not in the numbers seen in this case. Placental dissemination of a congenital
small round blue cell tumor is a very rare finding, and would appear as a more homogeneous cellular
population, often with clumping. Congenital acute leukemia (excluding cases of transient abnormal
myelopoiesis) in the placenta is a very rare finding as well, and uncommonly megakaryocytic in
differentiation.
Final Diagnosis:
Transient abnormal myelopoiesis of Down Syndrome, manifest as fetal thrombotic vasculopathy (multiple
chorionic plate and stem villous vessel thrombi).
Case Discussion:
This case demonstrates large vessel fetal thrombotic vasculopathy with a striking
cellularity of the thrombi, including a primitive cellular component. Expression of LAT on the primitive
cells, a marker of megakarocytic differentiation, strongly suggests transient abnormal myelopoiesis of
Down Syndrome. Subsequent karyotypic evaluation of the infant confirmed the diagnosis of trisomy 21. The blast proliferation resolved in
this infant. His clinical course never warranted chemotherapeutic intervention.
Discussion
General surgical pathologists are generally less familiar with the changes of fetal thrombotic
vasculopathy (FTV). Beyond recognition of the lesions, a further hurdle is being able to give the
findings an appropriate clinico-pathologic correlation. "Fetal thrombotic vasculopathy" is a diagnostic
term encompassing a spectrum of large and small vessel changes in the fetal placental and umbilical cord
vasculature. The changes are well illustrated in the SPP consensus paper on FTV (ref. 1).
The various causes of FTV are summarily explained by Virchow's triad (blood stasis, endothelial injury
and a hypercoagulable state). Most cases are associated with blood stasis, due to umbilical cord factors
or poor cardiac output. In some cases the changes (excluding true thrombi) are due to cessation of fetal
blood flow after fetal demise, and are more appropriately termed "involutional" rather than FTV. A
subset of FTV is associated with endothelial injury in cases of amniotic fluid infection with a severe
fetal inflammatory response (umbilical or chorionic plate vasculitis). Stem villous and terminal villous
FTV changes are also commonly seen in chronic villitis. However, while chronic villitis appears to
target and obliterate the fetal vasculature of affected villi, this process does not typically result in
thrombi of the affected villi. Villi distal to those affected by chronic villitis will manifest FTV
because fetal perfusion has ceased. The literature refers to these features as "associated fetal
vasculopathy" deleting the descriptor "thrombotic" from such cases. The hypercoagulable state causes of
FTV are often associated with gestational diabetes and erythrocytosis. In some cases FTV is associated
with an inherited thrombophilia in the fetus. One study of 65 archived placentas with FTV identified
Factor V Leiden heterozygous mutations in 18.5%, compared to <5% of controls. No Prothrombin G20210A
mutations were found. FTV is often a harbinger of poor outcome in the neonate. In cases of cardiac
failure, FTV may reflect a neonate in the process of dying. In other cases, FTV may mirror the presence
of systemic thrombi, especially cerebrovascular. Cases of amniotic fluid infection or chronic villitis
severe enough to manifest FTV or fetal vasculopathy are associated with worsened clinical outcomes as
well.
An uncommon, but clinically significant cause of FTV
This case demonstrates large vessel obstruction (chorionic plate and stem villous vasculature) due to
the hyperviscous state of transient abnormal myelopoiesis (TAM) in a Down syndrome (DS) neonate. The
presence of numerous megakaryoblasts in the fetal vasculature should strongly suggest the possibility of
TAM and warrant a cytogenetic evaluation of the infant for Trisomy 21. The extra chromosome 21 leads to
a proliferative advantage of hematopoietic precursors in vitro, consistent
with observations of polycythemia or thrombocytosis in DS patients resolving soon after birth. In
approximately 5% of DS neonates, a mutation of GATA1 is acquired in utero.
A somatic splice mutation in exon 2 leads to production of the GATA-1s
isoform, causing a proliferation of fetal, but not adult type, megakaryocytes. The peripheral blood
resembles an acute megakaryoblastic leukemia. However, in 80-90% of the infants with TAM, the
proliferation spontaneously resolves.
While TAM belongs to the unusual family of congenital tumors that may show spontaneous resolution
(e.g. stage 4S neuroblastoma) without chemotherapy, the proliferation is not necessarily benign. The
majority of cases may be asymptomatic, and never come to clinical attention, but a subset develop
life-threatening microembolic disease causing respiratory failure. In addition, the megakaryoblast
proliferation in the liver, and other extramedullary sites is associated with organomegaly and fibrosis
that may compromise organ function.
The Children's Oncology Group studied the natural history of 135 DS neonates with TAM. Most patients
presented at 5 days of age with a median of 25% blasts in the peripheral blood. RBC and platelet values
were variable with near normal indices. Approximately 20% of patients in the cohort required low-dose
chemotherapy intervention for hyperviscosity, blasts over 100,000/uL, organomegaly with respiratory
compromise, renal dysfunction or disseminated intravascular coagulation. The study identified three risk
groups, as outlined below:
| | Clinical features | Percentage of patients | Overall survival |
| Low risk | No palpable hepatomegaly or organ dysfunction | 38% | 92 +/- 8% |
| Intermediate risk | Hepatomegaly with non-life threatening hepatic dysfunction | 40% | 77 +/-12% |
| High risk | WBC >100K, or life threatening cardio-respiratory compromise due to TAM | 21% | 51 +/-19% |
The median time to resolution of the abnormal blast proliferation was 46 days in this study. In a
subset of DS neonates with TAM, the blast proliferation does not resolve and they go on to develop a DS
associated myelodysplastic syndrome and/or acute megakaryoblastic leukemia. The karyotype and
immunophenotype of TAM blasts and DS associated AMkL are virtually indistinguishable. By convention, the
diagnosis of acute megakaryoblastic leukemia (AMkL) is not given in the DS neonate until after the age of
3 months, to allow for recognition of those cases of TAM that will spontaneously resolve. In the COG
prospective study, 16% of the cohort developed AMkL, at a median of 441 days. Younger DS patients with
AMkL have an excellent survival with chemotherapy approaching 90%. Survival is poorer for patients 2-4
years of age (approximately 70%), and those over the age of 4 (30%).
References:
- Redline RW, Ariel I, Baergen RN, Desa DJ, Kraus FT, Roberts DJ, Sander CM. Fetal vascular obstructive lesions: nosology and reproducibility of placental reaction patterns. Pediatr Dev Pathol. 2004 Sep-Oct;7(5):443-52.
- Redline RW. Clinical and pathological umbilical cord abnormalities in fetal thrombotic vasculopathy. Hum Pathol. 2004 Dec;35(12):1494-8.
- Redline RW. Severe fetal placental vascular lesions in term infants with neurologic impairment. Am J Obstet Gynecol. 2005 Feb;192(2):452-7.
- Dahms BB, Boyd T, Redline RW. Severe perinatal liver disease associated with fetal thrombotic vasculopathy. Pediatr Dev Pathol. 2002 Jan-Feb;5(1):80-5.
- Vern TZ, Alles AJ, Kowal-Vern A, Longtine J, Roberts DJ. Frequency of factor V(Leiden) and prothrombin G20210A in placentas and their relationship with placental lesions. Hum Pathol. 2000 Sep;31(9):1036-43.
- Heerema-McKenney A, Arber D "Chapter 50, "Myeloid Proliferations related to Down Syndrome", in Kjeldsberg CR and Perkins SL (eds.): Practical Diagnosis of Hematologic Disorders, 5th edition, Vol. 2, pages 639-644.ASCP Press, Chicago, IL, 2010.
- Gamis AS, Alonzo TA, Gerbing RB, Hilden JM, Sorrell AD, Sharma M, Loew TW, Arceci RJ, Barnard D, Doyle J, Massey G, Perentesis J, Ravindranath Y, Taub J, Smith FO. Natural history of transient myeloproliferative disorder clinically diagnosed in Down syndrome neonates: a report from the Children's Oncology Group Study A2971. Blood. 2011 Dec 22;118(26):6752-9.
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