Acute erythroid leukemia.

CONTEXT: Acute erythroid leukemia (AEL) is an uncommon type of acute myeloid leukemia (AML), representing less than 5% of all cases. Acute erythroid leukemia is characterized by a predominant erythroid proliferation, and in the current World Health Organization (WHO) classification scheme there are 2 subtypes: erythroleukemia (erythroid/myeloid leukemia) and pure erythroid leukemia. Morphologic findings are most important for establishing the diagnosis. The erythroleukemia subtype, which is most common, is defined as the presence of 50% or more erythroid precursors and 20% or more blasts in the nonerythroid component. The pure erythroid leukemia subtype is composed of 80% or more immature erythroblasts. Although these morphologic criteria appear straightforward, AEL overlaps with other types of AML and myelodysplastic syndrome that are erythroid rich. OBJECTIVE: To provide an update of AEL, including clinical presentation, morphologic features, immunophenotype, and cytogenetic and molecular data. As the erythroleukemia subtype is most common, the literature and this review are biased towards this subtype of AEL. DATA SOURCES: Clinicopathologic, cytogenetic, and molecular information were extracted from our review of pertinent literature and a subset of AEL cases in the files of The University of Texas M. D. Anderson Cancer Center (Houston) and University of South Alabama (Mobile). CONCLUSIONS: The current WHO criteria for establishing the diagnosis of AEL reduce the frequency of this entity, as cases once classified as the erythroleukemia subtype are now reclassified as other types of AML, particularly AML with myelodysplasia-related changes and therapy-related AML. This reclassification also may have prognostic significance for patients with the erythroleukemia subtype of AEL. In contrast, the current WHO criteria appear to have little impact on the frequency and poor prognosis of patients with the pure erythroid leukemia subtype of AEL. Molecular studies, preferably using high-throughput methods, are needed for a better understanding of the pathogenesis of AEL, and for developing diagnostic and prognostic markers.

Acute erythroid leukemia as defined in the World Health Organization classification is a rare and pathogenetically heterogeneous disease.

The diagnostic criteria for acute erythroid leukemia have been controversial since this disease was initially described. Using the current World Health Organization classification criteria, we retrospectively reviewed cases of acute myeloid leukemia or myelodysplastic syndrome in which erythroid precursors were >or=50% of the bone marrow nucleated cell population and the diagnosis of erythroleukemia was considered using older classification schemes. We collected 90 cases and separated them into four diagnostic groups: acute erythroid leukemia, erythroleukemia or erythroid/myeloid type (n=20); acute myeloid leukemia with myelodysplasia-related changes (n=22); therapy-related acute myeloid leukemia (n=32); and refractory anemia with excess blasts and preceding or concurrent history of erythropoietin therapy for anemia (n=16). Patients with acute erythroid leukemia were the youngest patient group and had the best overall survival. There was a statistically significant difference in overall survival between patients with acute erythroid leukemia versus acute myeloid leukemia with myelodysplasia-related changes (P=0.003) and between patients with acute erythroid leukemia versus therapy-related acute myeloid leukemia (P<0.0001). The presence of complex cytogenetic abnormalities (>3) was the only statistically significant independent variable that adversely affected survival in the acute erythroid leukemia group. Monosomy 5/del(5q) and monosomy 7/del(7q) were overrepresented in the context of complex chromosomal abnormalities. Our data suggest that acute erythroid leukemia, as currently defined in the World Health Organization classification, has become a rare disease. A majority of the cases reported previously as erythroleukemia are now classified as other entities. In addition, our data suggest that the current definition of acute erythroid leukemia, erythroleukemia type remains heterogeneous. One subset of acute erythroid leukemia patients has relatively low blast counts and are diploid. The prognosis of this patient subset is relatively good. The other subset has cytogenetic abnormalities similar to those in myelodysplastic syndromes and a poor prognosis.

Treatment of benign lymphoid hyperplasia of the orbit with rituximab.

Benign lymphoid hyperplasia is a disorder characterized by polyclonal lymphocytic infiltration of orbital tissues, predominantly with B-cells. Rituximab is a monoclonal antibody directed against CD20, a B-cell marker. Two patients with recurrent orbital masses involving the lacrimal glands were treated with rituximab. The diagnosis of benign lymphoid hyperplasia with predominance of CD20 cells was confirmed in both cases based on a surgical biopsy. Both patients had been previously treated with standard therapies, including high-dose steroids, and one patient had failed external-beam radiation therapy. They both responded well to treatment with intravenous rituximab. Neither patient experienced any side effects associated with rituximab.

Acute erythroid leukemia: a reassessment using criteria refined in the 2008 WHO classification.

Acute erythroid leukemia (AEL) is a rare type of acute myeloid leukemia (AML) for which diagnostic criteria have been refined in the 2008 World Health Organization (WHO) classification of AML. The relationship of AEL to myelodysplastic syndromes (MDSs) and to AML with myelodysplasia-related changes (AML-MRC) is not clearly defined. We conducted a retrospective, multi-institutional study of patients with AEL and compared them with patients with MDS or AML-MRC with erythroid hyperplasia (> or = 50% erythroid cells). Among a total of 124 patients with AEL, 32% had a history of MDS or chronic cytopenia, 32% had therapy-related disease, and 35% had de novo disease. Sixty-four percent of patients had unfavorable AML risk-group karyotypes. FLT3 and RAS mutations were infrequent, occurring in 6% and 2%, respectively. The median overall survival (OS) of all AEL patients was 8 months, comparable with that of patients with MDS or AML-MRC with erythroid hyperplasia. The OS was related to cytogenetic risk group, but not blast count or morphologic dysplasia. Our findings suggest that AEL is in the continuum of MDS and AML with erythroid hyperplasia, where karyotype rather than an arbitrary blast cutoff represents the most important prognostic factor.

Genetic haploinsufficiency as a phenotypic determinant of a deletion 13q syndrome.

Two cases of newborns with deletion 13q syndrome were identified and studied using electron microscopy and histologic, immunohistochemical, and special stained sections. We reviewed the published literature on genes that are haploinsufficient in the deletion 13q syndrome. The complexity of the deletion 13q syndrome phenotype is due at least in part to the haploinsufficiency of dosage-sensitive genes. Future studies need to be performed to identify their precise role in the cellular function and the development of the deletion 13q syndrome phenotype.

Ex vivo expression of angiogenic growth factors and their receptors in human penile cavernosal cells.

Arteriogenic erectile dysfunction is associated with impairment of vascular perfusion to the erectile components of the penis. Animal studies have identified insulin-like growth factor (IGF-I) and vascular endothelial growth factor (VEGF) as penile angiogenic growth factors, but the role of these factors in humans is not well understood. We evaluated the ex vivo expression of IGF-I, VEGF, and their receptors (IGF-IR, Flt-1, and KDR) in human penile cavernosal smooth muscle cells (HCSMCs) to identify cellular and molecular pathways involved in the regulation of penile tissue vascularity. Primary culture was initiated with explants of human corpora cavernosa, and early passage (3-5) cells were used for these evaluations. Cultures were examined to verify the presence of smooth muscle cells and the absence of endothelial cell contamination. Specific monoclonal antibodies were used to localize growth factors and their receptors. To evaluate gene expression of VEGF, Flt-1, and KDR, total RNA was extracted from cavernosal cells and subjected to reverse transcriptase-polymerase chain reaction (RT-PCR) using custom synthesized primers. To study the effect on cell proliferation, 10000 cells/well were exposed to varying concentrations of VEGF (0-50 ng/mL). At specified time periods the cells were trypsinized and counted. IGF-I and VEGF and their receptors were localized in the cultures, which were positive for the presence of smooth muscle cells and negative for endothelial cell contamination. RT-PCR evaluation revealed the expression of four splice variants of VEGF messenger RNA (VEGFs 121, 145, 165, and 189) and two of its receptors (Flt-1 and KDR). VEGF165 and VEGF121 were the most abundant forms of messenger RNA and Flt-1 appeared to be the most prominent receptor type in these cells. Exposure to VEGF elicited a twofold to threefold increase in the proliferation of HCSMCs. HCSMCs express both IGF-I and VEGF and their receptors, which may be important in the control of vascularity in human penile architecture.

Small intestinal submucosa as a tunica albuginea graft material.

PURPOSE: We evaluated the morphological, immunological and functional response to small intestinal submucosa grafting of the tunica albuginea to determine its potential as a grafting material for penile surgery. MATERIALS AND METHODS: Male New Zealand White rabbits underwent a sham procedure (6) or tunical excision and grafting with small intestinal submucosa (6). The erectile response to the intracavernous vasoactive agents sodium nitroprusside plus a papaverine, phentolamine and prostaglandin E1 combination (Sigma Chemical Co., St. Louis, Missouri) was evaluated 45-day postoperatively. The area under the graft was evaluated for stromal collagen and smooth muscle content by Masson's trichrome stain. Protein expression of smooth muscle specific alpha-actin and the inflammatory markers inducible nitric oxide synthase (NOS) and transforming growth factor-beta1 (TGF-beta1) was evaluated by immunohistochemical methods. Total RNA was extracted from the corpora cavernosum underlying the small intestinal submucosa graft and reverse transcriptase-polymerase chain reaction (RT-PCR) was done using an Access system (Promega, Madison, Wisconsin) with gene specific primers for inducible NOS, TGF-beta1 and vascular endothelial growth factor (VEGF). RESULTS: Grafting of the tunica albuginea with small intestinal submucosa had no significant effect on the magnitude or duration of the erectile response to intracavernous vasoactive agents. Histological examination demonstrated no inflammatory changes in the tunica albuginea or corporeal tissue underlying the area of the small intestinal submucosa graft and there was no appreciable alteration in smooth muscle or collagen content. The 2 groups showed intense positive immunostaining to alpha-actin. Weak expression of TGF-beta1 predominantly associated with smooth muscle fibers was identified in the 2 groups of rabbits by immunostaining and RT-PCR. No significant inducible NOS was detected by immunostaining or RT-PCR in either group. Strong VEGF expression was observed in grafted rabbits. The most noticeable (3-fold) increase in expression was detected in splice variant 165. CONCLUSIONS: Small intestinal submucosa grafting of the tunica albuginea preserves the duration and magnitude of the erectile response to vasoactive agents. This type of tunical grafting does not stimulate a significant inflammatory response, or cause corporeal fibrosis or loss of cavernous smooth muscle content. Stimulating VEGF may facilitate wound healing and the maintenance of normal erectile function.

Altered growth factor expression in the aging penis: the Brown-Norway rat model.

The objective of the present study was to evaluate age-related changes in the protein and gene expression of modulators of erectile function (nitric oxide [NO] and endothelin-1 [ET-1]) and growth factors such as transforming growth factor (TGF-beta1) and vascular endothelial growth factor (VEGF) in the penile tissue of Brown-Norway (BN) rats. Young and old BN male rats were euthanized, and the penile tissue was processed for immunohistochemical and molecular analyses. Total RNA was extracted, and an Access reverse transcription-polymerase chain reaction (RT-PCR) system was used for messenger RNA (mRNA) expression analysis. Immunohistochemical studies showed a decreased expression of endothelial nitric oxide synthase (eNOS) protein and an increased staining for ET-1. Quantitative analysis of PCR products revealed decreased levels of VEGF mRNA expression in the old population of rats. The most significant decrease was detected between bands corresponding to splice forms 164 (21%) and 120 (18%). The observed alterations in the gene expression of growth factors such as VEGF may contribute to the abnormal age-related morphological and physiological alterations in the erectile tissue.