Paraneoplastic leukemoid reaction: Case report and review of the literature.

OBJECTIVES: We recently encountered a patient with unexplained hyperleukocytosis (105.4 K/µL at presentation), subsequently found to have colon cancer with a marked tumor-associated neutrophilic infiltrate; the leukocytosis abruptly improved after tumor removal. Paraneoplastic leukemoid reaction (PLR) is a rare entity, occurring due to tumor cytokine secretion (typically granulocyte-colony stimulating factor [G-CSF]). We describe a case and aggregate results of previously published cases. METHODS: We reviewed the English-language literature for all prior reports of PLR, recording age, gender, histologic diagnosis, WBC count, G-CSF level, and overall survival. We analyzed clinicopathologic variables' impact on survival. RESULTS: We identified 179 cases (mean age 64; 72 % M). Adeno-, squamous cell, sarcomatoid, and undifferentiated carcinomas accounted for >70 %. Esophagus, gallbladder, lung, liver, and pancreas were the most common primaries. At time of publication 81 % of patients had died, with mean overall survival of 4 months. There was no correlation between WBC count and G-CSF level. On univariate analysis, WBC count was the only variable associated with survival (P = 0.03). Patients with WBC counts >100 K/µL were twice as likely to die as those with counts from 11 K to 40 K/µL. CONCLUSIONS: PLR, typically carcinoma-associated, is characterized by dismal prognosis. The WBC count is inversely related to survival. Knowledge of this phenomenon militates against protracted, expensive work ups. In malignant neoplasms with prominent neutrophilic stroma, the pathologist should correlate with the WBC count and, if markedly elevated (>40 K/µL), raise consideration for PLR.

MicroRNA-155-5p Plays a Critical Role in Transient Leukemia of Down Syndrome by Targeting Tumor Necrosis Factor Receptor Superfamily Members.

BACKGROUND/AIMS: Down syndrome associated disorders are caused by a complex genetic context where trisomy 21 is a central component in relation to other changes involving epigenetic regulators and signaling molecules. This unique genetic context is responsible for the predisposition of people with Down syndrome to acute leukemia. Although, the research in this field has discovered some important pathogenic keys, the exact mechanism of this predisposition is not known. METHODS: In this study we applied functional enrichment analysis to evaluate the interactions between genes localized on chromosome 21, genes already identify as having a key role in acute leukemia of Down syndrome, miRNAs and signaling pathways implicated in cancer and cell development and found that miR-155 has a high impact in genes present on chromosome 21. Forward, we performed next generation sequencing on DNA samples from a cohort of patients diagnosed with acute leukemia of Down syndrome and in vitro functional assay using a CMK-86 cell line, transfected with either mimic or inhibitor of the microRNA-155-5p. RESULTS: Our results show that the epigenetic alteration of the TNF superfamily receptors in Down syndrome, which can be correlated to microRNA-155-5p aberrant activity, may play an important role in cell signaling and thus be linked to acute myeloid leukemia. CONCLUSION: Some genes, already shown to be mutated in AML-DS, are potential targets for miR-155. Our results show that the epigenetic alteration of the TNF superfamily receptors in Down syndrome may play an important role in cell signaling and thus be linked to acute myeloid leukemia.

Placental Pathology in Down Syndrome-Associated Transient Abnormal Myelopoiesis.

Transient abnormal myelopoiesis is a hematopoietic disorder that occurs in up to 10% of neonates with Down syndrome. It is characterized by leukocytosis and the presence of circulating blast cells harboring truncating GATA1 mutations with variable multiorgan system involvement. Placental involvement of transient abnormal myelopoiesis is infrequently described. Placental examination and identifying features related to transient abnormal myelopoiesis could be one of the early, if not the only, means of diagnosis of this condition in affected stillbirths, premature infants, and a subset of asymptomatic neonates. This article provides an overview of the placental pathology in transient abnormal myelopoiesis with review of the literature, and also discusses the important differential diagnoses.

Loss of Full-Length GATA1 Expression in Megakaryocytes Is a Sensitive and Specific Immunohistochemical Marker for the Diagnosis of Myeloid Proliferative Disorder Related to Down Syndrome.

OBJECTIVES: Myeloid proliferative disorders associated with Down syndrome (MPD-DS), including transient abnormal myelopoiesis and myeloid leukemia associated with Down syndrome (DS), harbor mutations of GATA1, a transcription factor essential for erythroid and megakaryocytic development. These mutations result in a N-terminally truncated GATA1 (GATA1s) and prohibit the production of the full-length GATA1 (GATA1f). Here, we demonstrate the utility of immunohistochemical GATA1f reactivity in diagnosing MPD-DS. METHODS: Immunohistochemical studies for GATA1f expression were performed on bone marrow biopsy specimens. RESULTS: In all cases of MPD-DS, megakaryocytes lacked GATA1f expression. In contrast, GATA1f expression was detected in megakaryocytes in all specimen types from patients without DS (normal bone marrows, pediatric myelodysplastic syndrome, juvenile myelomonocytic leukemia, adult acute megakaryocytic leukemia [pediatric and adult; without trisomy 2]), as well as normal bone marrows from patients with DS. CONCLUSIONS: The lack of GATA1f expression is a sensitive and specific immunohistochemical marker for MPD-DS.

Preleukemic phase of chronic myelogenous leukemia: morphologic and immunohistochemical characterization of 7 cases.

Patients with chronic myelogenous leukemia (CML) present typically with an elevated white blood cell count (WBC) and cytogenetic or molecular genetic evidence of t(9;22)/BCR-ABL1 fusion gene. Rarely, CML patients may present with a normal or mildly elevated WBC and are asymptomatic, and we describe 7 patients in this study. The WBC in these patients ranged from 3.6 to 14.3 K/mm(3) with 50% to 73% granulocytes and 0% blasts. In all patients, t(9;22)(q34;q11.2) was detected by conventional cytogenetics, and BCR-ABL1 fusion was shown, supporting the diagnosis of preleukemic CML (pre-CML). We compared these patients with a group of 5 cases of CML in chronic phase (CML-CP) and 5 bone marrow specimens with a leukemoid reaction (n=5). Reticulin, CD34, and CD61 immunostains were performed on all bone marrow biopsy specimens. Peripheral blood absolute basophilia (≥200/mm(3)) was noted in only 4 of 7 pre-CML cases, whereas it was present in all CML-CP cases and absent in leukemoid reaction cases. The mean ±SD of microvascular density of pre-CML cases (10.0 ± 4.3 vessels/200× field) was twice that of leukemoid reaction cases (5.0 ± 1.0) (P=.02; Student t test) but similar to that of CML-CP cases (12.5 ± 3.6). Microvessels in pre-CML, highlighted by CD34, were tortuous with abnormal branching, although to a lesser extent than those found in CML-CP. Microvessels in leukemoid reaction were generally straight. The percentage of small, hypolobated megakaryocytes, highlighted by CD61 in pre-CML, was 40%, 3 times that found in leukemoid reaction cases (13%) but less than that of CML-CP cases (86%). We conclude that pre-CML should be suspected in patients with a normal to mildly elevated WBC and absolute basophilia. Bone marrow examination can usually distinguish pre-CML from a leukemoid reaction based on the percentage of small, hypolobated megakaryocytes; microvascular density; and morphologic features.

EphA4-deleted microenvironment regulates cancer development and leukemoid reaction of the isografted 4T1 murine breast cancer via reduction of an IGF1 signal.

UNLABELLED: EphA4 belongs to the largest family of receptor tyrosine kinases (RTKs). Although EphA4 is highly expressed in the central nervous system, EphA4 has also been implicated in cancer progression. Most of the studies focus on the expression and function in tumor cells. It is unknown whether EphA4-deleted microenvironment affects tumor progression. Some of cancers in animals and humans, such as 4T1 cancer cells, are known to produce a large amount of granulocyte colony-stimulating factors (G-CSF/Csf3) which can stimulate myeloproliferation, such as myeloid-derived suppressor cells (MDSCs) leading to a poor recipient prognosis. We isografted 4T1 breast cancer cells into both EphA4-knockout and control wild-type female littermate mice. The results showed that the EphA4-deleted host could inhibit primary tumor growth and tumor metastasis mainly by decreasing the amount of IGF1 synthesis in the circulation and locally tissues. The EphA4-deleted microenvironment and delayed tumor development reduced the production of G-CSF resulting in the decrease of splenomegaly and leukemoid reaction including MDSCs, which in turn inhibit the tumor progression. This inhibition can be reversed by supplying the mice with IGF1. However, an excess of IGF1 supply over demand to the control mice could not further accelerate the tumor growth and metastasis. A better understanding and re-evaluation of the main role of IGF1 in regulating tumor progression could further enhance our cognition of the tumor development niche. Our findings demonstrated that EphA4-deleted microenvironment impairs tumor-supporting conditions. CONCLUSION: Host EphA4 expression regulates cancer development mainly via EphA4-mediated IGF1 synthesis signal. Thus, targeting this signaling pathway may provide a potential therapeutic option for cancer treatment.

PRAME immunohistochemical staining in transient abnormal myelopoiesis and myeloid leukemia associated with Down syndrome.

Transient abnormal myelopoiesis (TAM) and myeloid leukemia associated with Down syndrome (ML of DS) have morphologically indistinguishable blasts. TAM usually presents and regresses within the first three months of life. In a subset of patients, myelopoiesis remains abnormal, and the persistence of elevated blasts after 6 months is considered ML of DS. Current tools including cytogenetics and flow cytometry fail to distinguish blasts of TAM that will regress from blasts of ML of DS. One gene expression profiling study suggested PRAME expression was significantly increased in ML of DS compared to TAM. To further investigate this finding, we studied PRAME protein expression by immunohistochemistry in cases of TAM and ML of DS. PRAME immunoreactivity was found in blasts, dysplastic megakaryocytes, and fibroblasts. Four cases of TAM and fourteen cases of ML of DS had interpretable staining, with PRAME cytoplasmic reactivity in megakaryoblasts. Of the four cases of TAM, two were positive for PRAME; of the two patients, one had follow-up demonstrating ML of DS and the other had fully regressing TAM. Of the fourteen cases of ML of DS, ten had at least a subset of cells with positive PRAME staining, while four were negative for PRAME. In summary, PRAME immunoreactivity in ML of DS is largely due to the non-blast components, while PRAME immunoreactivity in blasts of TAM is not restricted to cases that progress to ML of DS.

Transient abnormal myelopoiesis in non-Down syndrome neonate.

We encountered a case of neonatal acute megakaryoblastic leukemia not associated with Down syndrome (DS). Molecular cytogenetic analysis of leukemic blast cells indicated that increased blast cell status was caused by transient abnormal myelopoiesis with trisomy 21 and GATA1 mutation. Based on these molecular cytogenetic data, intensive chemotherapy was avoided, and the patient was successfully cured with low-dose cytarabine. Morphologically, leukemic blast cells of acute megakaryoblastic leukemia in a non-DS neonate are indistinguishable from a blast cell of transient abnormal myelopoiesis. The possibility of transient abnormal myelopoiesis should be carefully considered before intensive chemotherapy is adopted.

Fetal liver stromal cells support blast growth in transient abnormal myelopoiesis in Down syndrome through GM-CSF.

Transient abnormal myelopoiesis (TAM) in neonates with Down syndrome, which spontaneously resolves within several weeks or months after birth, may represent a very special form of leukemia arising in the fetal liver (FL). To explore the role of the fetal hematopoietic microenvironment in the pathogenesis of TAM, we examined the in vitro influences of stromal cells of human FL and fetal bone marrow (FBM) on the growth of TAM blasts. Both FL and FBM stromal cells expressed mesenchymal cell antigens (vimentin, α-smooth muscle actin, CD146, and nestin), being consistent with perivascular cells/mesenchymal stem cells that support hematopoietic stem cells. In addition, a small fraction of the FL stromal cells expressed an epithelial marker, cytokeratin 8, indicating that they could be cells in epithelial-mesenchymal transition (EMT). In the coculture system, stromal cells of the FL, but not FBM, potently supported the growth of TAM blast progenitors, mainly through humoral factors. High concentrations of hematopoietic growth factors were detected in culture supernatants of the FL stromal cells and a neutralizing antibody against granulocyte-macrophage colony-stimulating factor (GM-CSF) almost completely inhibited the growth-supportive activity of the culture supernatants. These results indicate that FL stromal cells with unique characteristics of EMT cells provide a pivotal hematopoietic microenvironment for TAM blasts and that GM-CSF produced by FL stromal cells may play an important role in the pathogenesis of TAM.

Transient leukemia in a newborn without Down syndrome: case report and review of the literature.

UNLABELLED: Transient neonatal leukemia occurs almost exclusively in Down syndrome babies. We report here the unusual case of a newborn without Down syndrome who presented neonatal transient leukemia and who achieved spontaneously complete remission. Trisomy 21 and GATA1 mutation were both present in leukemic cells. While close follow-up is advised since true leukemia may develop later, the patient is still in remission for 2.5 years. We performed a literature review of 15 other similar cases. CONCLUSION: Our case of transient leukemia without Down syndrome and the literature review highlight the important role of trisomy 21 and GATA1 mutation in the development of transient neonatal leukemia.

Leukaemoid reaction with megakaryocytic features in newborns with Down's syndrome.

A leukaemoid reaction was observed in 3 newborns with Down's syndrome. Thrombocytopenia was present in 2, requiring platelets transfusions in 1, and red cell transfusions were necessary in 2 patients. Blast cells characterization by specific monoclonal antibodies showed a prevalence of megakaryoblasts in all 3 cases. This feature was confirmed in 2 of them by the demonstration of platelet peroxidase (PPO) activity under transmission electron microscopy (TEM). A spontaneous remission of the leukaemoid picture was observed after 2-3 months. However, in 1 case a relapse of the myeloproliferative disorder with the same features of the blast cell population was diagnosed after 16 months. Chemotherapy with low-dose Ara-C, started because of a relevant clinical involvement, induced a complete remission.