Background
The myelodysplastic syndromes (MDS) are a group of bone marrow disorders usually presenting with symptoms related to deficiencies of one or more of the bone marrow elements. Anemia, bleeding problems, and infections are all presenting symptoms. The diagnosis can only be made by the pathologist by examining a bone marrow aspirate and biopsy.
OUTLINE
DISEASE ASSOCIATIONS CHARACTERIZATION LANGERHANS CELL HISTIOCYTOSIS
- Langerhans cell histiocytosis associated with myelodysplastic syndrome in adults.
Billings SD, Hans CP, Schapiro BL, Martin RW 3rd, Fivenson D, Fruland JE, Moores WB, Cotton J.
Departments of Pathology and Dermatology, Indiana University School of Medicine, Indianapolis, IN.
J Cutan Pathol. 2006 Feb;33(2):171-4. Abstract quote
Background: Myelodysplastic syndrome (MDS) is a group of bone marrow disorders associated with dyplasia of myeloid elements that may have cutaneous manifestations including infections, vasculitis, Sweet's syndrome, pyoderma gangrenosum, erythema elevatum diutinum, and leukemia cutis. These cutaneous manifestations are attributed to the underlying bone marrow defect. Langerhans cell histiocytosis (LCH) is primarily a pediatric disease, and rarely LCH has been described in association with pediatric MDS. We are aware of only a single case report of LCH associated with MDS in an adult.
Methods: We report two new cases of LCH in elderly patients with underlying MDS. The specimens were examined by routine microscopy as well as immunohistochemical stains for S100 protein and CD1a.
Results: Both patients were elderly men with established diagnoses of MDS. One presented with a solitary pruritic papule while the other had a 2-year history of erythematous papules involving the trunk and extremities. Histologic examination revealed intraepidermal and dermal collections of mononuclear cells with reniform nuclei. The cells were strongly positive for S100 and CD1a, confirming their identity as Langerhans cells.
Conclusion: Cutaneous LCH may be associated with underlying MDS in adults and should be considered in the differential diagnosis of cutaneous eruptions in patients with MDS.RELAPSING POLYCHONDRITIS Myelodysplastic syndrome associated with relapsing polychondritis: unusual transformation from refractory anemia to chronic myelomonocytic leukemia.
Shirota T, Hayashi O, Uchida H, Tonozuka N, Sakai N, Itoh H.
Department of Internal Medicine, Tokyo Medical College Hospital, Japan.
Ann Hematol 1993 Jul;67(1):45-7 Abstract quote
The authors report an unusual case of myelodysplastic syndrome (MDS) associated with relapsing polychondritis (RP), which developed at almost the same time as MDS.
The initial diagnosis was MDS, refractory anemia (RA) subtype, according to the FAB classification. Symptoms of RP were apparently controlled by oral administration of prednisolone (PSL), although MDS was not. Within 1 month after the diagnosis, monocytosis and thrombocytopenia without excess of blasts became prominent and transformation from RA to chronic myelomonocytic leukemia (CMML) was recognized. Combination chemotherapy including daunorubicin (DNR) and cytosine arabinoside (ara-c) did not subdue the progressive monocytosis and thrombocytopenia. Finally, the patient died of pulmonary hemorrhage 3 months after the onset of the disease.
The prognosis of MDS may be poorly influenced by association with RP.
Association of myelodysplastic syndrome and relapsing polychondritis: further evidence.
Hebbar M, Brouillard M, Wattel E, Decoulx M, Hatron PY, Devulder B, Fenaux P.
Department of Internal Medicine, CHU, Lille, France.
Leukemia 1995 Apr;9(4):731-3 Abstract quote
We report five patients with both a myelodysplastic syndrome (MDS) and relapsing polychondritis (RP), that represented 0.6% of all MDS and 28% of all RP diagnosed over a period of 14 years.
Ten other cases had previously been reported (four in detail), supporting a non-fortuitous association between the two disorders, already suggested for MDS and some other immunological disorders.
Relapsing polychondritis, smouldering non-secretory myeloma and early myelodysplastic syndrome in the same patient: three difficult diagnoses produce a life threatening illness.
Hall R, Hopkinson N, Hamblin T.
Department of Rheumatology and Haematology, Royal Bournemouth Hospital, UK.
Leuk Res 2000 Jan;24(1):91-3 Abstract quote
Multiple myeloma, relapsing polychondritis and myelodysplastic syndrome are all serious diseases in which making a clear diagnosis can be difficult.
This case of a 72-year-old man found after extensive investigation to have all three of the above, demonstrates how difficult diagnosis and treatment can be, producing in this case a life threatening clinical syndrome.
We also postulate that the association of these three diseases may be an immune-derived complication of myelodysplastic syndrome.
CHARACTERIZATION CHROMOSOMAL ABNORMALITIES70-80% of cases FavorableNormal chromosomes
5q-(Single defect) Intermediate+8 UnfavorableComplex defects
Monosomy 7 or 7q-
LABORATORY/
RADIOLOGIC/
OTHER TESTSCHARACTERIZATION General Variable findings depending upon the cell line affected and variant of MDS FLOW CYTOMETRY
- Four-color flow cytometry shows strong concordance with bone marrow morphology and cytogenetics in the evaluation for myelodysplasia.
Kussick SJ, Fromm JR, Rossini A, Li Y, Chang A, Norwood TH, L Wood B.
Department of Laboratory Medicine, University of Washington, Seattle.
Am J Clin Pathol. 2005 Aug;124(2):170-81. Abstract quote
The ability of 4-color flow cytometry (FC) to help identify myelodysplastic syndromes (MDSs) was evaluated in 124 bone marrow aspirates from unselected patients with unexplained cytopenias and/or monocytosis.
The morphologic features of bone marrow aspirate smears were correlated with FC and cytogenetic findings blindly, and patterns of antigen expression were compared with patterns seen in nonneoplastic and normal marrow specimens. Of 124 cases, 58 (46.7%) had definitive FC abnormalities ("flow-abnormal"), 19 cases (15.3%) had mild FC abnormalities of indeterminate significance, and 47 cases (37.9%) had essentially normal FC.
Highly significant differences were identified between the flow-abnormal group and other groups in mean myeloid blast percentages and numbers of abnormal antigens expressed, even when the analysis was limited to cases with fewer than 5% myeloid blasts.
Strikingly, flow-abnormal cases constituted 50 (89%) of the 56 morphologically abnormal cases and 31 (94%) of the 33 cytogenetically abnormal cases, demonstrating the strong concordance of FC-identified antigenic abnormalities with morphologic features and cytogenetics in the evaluation of patients with unexplained cytopenias.
HISTOLOGICAL TYPES CHARACTERIZATION General MDS must show dysplastic changes in the myeloid cell lines which include the red blood cells, megakaryocytes, granulocytes, and monocytes
In general, severe fibrosis is uncommon. There is a rare variant of myelodsyplasia with myelofibrosis which is usually an aggressive disorder with a clinical course similar to acute myeloid leukemia
Refractory Anemia (RA) Normochromic normocytic to microcytic red blood cells
Ringed sideroblasts<15%
No peripheral blood blasts
Mild dyserythropoiesis
Bone marrow blasts<5%
Marked erythroid hyperplasiaRefractory anemia with ringed sideroblasts (RARS) >15% ringed sideroblasts in bone marrow
Erythroid hyperplasia in marrowRefractory anemia with excess of blasts (RAEB) 5-19% blasts in the bone marrow
Peripheral blood <5% blasts
Neutrophil abnormalities common
Usually hypercellular bone marrow with abnormal localization of immature precursors (ALIP)-immature myeloid cells are present in positions different from usual locations of paratrabecular or perivascular-three or more are associated with increased incidence of leukemic evolutionRefractory anemia with excess of blasts in transformation (RAEB-T) Similar changes as in RAEB except:
20-29% blasts in bone marrow
5-29% blasts in peripheral blood
Auer rods in myeloblasts or other cells of the neutrophil cell lineAuer rods present in 70% of cases
Ringed sideroblasts may be numerousHypercellular marrow in 80-90% of cases
Chronic myelomonocytic leukemia (CMML) Must exclude CML and other myeloproliferative diseases first
Usually splenomegaly and elevated WBC count but Philadelphia chromosome negativeBone marrow blasts<20%
Peripheral blood blasts<5%
Absolute monocytes count of >1x10*9/L
Monocytes are NSE positive
(Note: If there is a high percentage of promonocytes, consider AML-M4 or M5)50% of patients will have polyclonal hypergammaglobulinemia
Mod Pathol. 2006 Dec;19(12):1536-45. Abstract quote
The World Health Organization criteria for diagnosing chronic myelomonocytic leukemia (CMML) are largely based on findings observed in the peripheral blood and bone marrow aspirate. A specific diagnostic role for the bone marrow biopsy has not been adequately explored.
We examined whether bone marrow biopsy supplemented by immunohistochemistry may be helpful in distinguishing CMML from cases of chronic myelogenous leukemia and atypical chronic myeloid leukemia (aCML).
We immunostained 25 cases of CMML with paraffin reactive antibodies which included CD68 (KP1), CD68R (PG-M1), and CD163, and compared the results with those observed in six cases of chronic myelogenous leukemia and in three cases of atypical CML. In addition, we examined whether CD34 immunohistochemistry could be useful in separating cases of CMML with less than 10% blasts (type-1) from cases of CMML with blasts accounting for 10-19% (type-2), and cases of CMML in acute transformation to acute myeloid leukemia (blasts>/=20%).
The presence of nodules of plasmacytoid monocytes was investigated by CD123 staining. CD42b was used to highlight abnormal megakaryocytes. Our results demonstrate significant differences between the groups. CD34 analysis allowed separating CMML type-1 from type-2 and the former from CMML in acute transformation. CD123-positive plasmacytoid monocyte nodules were found only in CMML and not in the other two disease groups. Overlap between CMML and the other two groups were observed with CD68 immunostaining. CD68R was more restricted to bone marrow macrophages and monocytes than CD68, but the differences between CMML and chronic myelogenous leukemia or atypical CML were still not significant.
Although CD42b immunostaining facilitated the detection of dwarf megakaryocytes often present in CMML, the distinction between those and the small forms seen in chronic myelogenous leukemia was still problematic.Chronic myelomonocytic leukemia in transformation (CMML-T) Hematologic features of CMML and one or more of the three findings associated with RAEB-T
Auer rods are abundantMyelodysplastic syndrome, unclassifiable (MDS-U) Marrow blasts<5%
May have marked dysgranulopoiesis and dysmegakaryoctyopoiesis
Ringed sideroblasts may be present
Marrow usually hypercellular with panhyperplasia5q- syndrome Isolated 5q- chromosomal abnormality
(Usually 5q23-31 region)
Macrocytic anemia
Hypolobated megakaryocytes (</=3 lobes)
Prolonged clinical coursePatients with therapy related MDS or AML associated with 5q- have a poor prognosis with rapid progression and shorter survival times
Monosomy 7 Syndrome of childhood Median age 10 months
Males
Recurrent infections with splenomegalyHISTOLOGIC VARIANTS AUER RODS
- Low blast count myeloid disorders with auer rods: a clinicopathologic analysis of 9 cases.
Willis MS, McKenna RW, Peterson LC, Coad JE, Kroft SH.
Department of Pathology, University of Texas Southwestern Medical Center, Dallas.
Am J Clin Pathol. 2005 Aug;124(2):191-8. Abstract quote
Auer rods are a hallmark of acute myeloid leukemia but occasionally are seen in myelodysplastic syndromes (MDSs) or chronic myelomonocytic leukemia, rarely in cases with fewer than 5% blasts. The significance of this finding is unclear.
We report 9 cases of this unusual phenomenon. All patients had cytopenias, isolated to a single lineage in 4. Circulating blasts were present in 8 cases (rare to 2.5%). Bone marrow blasts ranged from 0.4 to 4.9%; 1% to 32% of blasts contained Auer rods. There were variable degrees of dysplasia; 1 case closely mimicked refractory anemia with ringed sideroblasts. Cytogenetic studies in 8 cases showed clonal changes in 4. In 5 patients, acute myelogenous leukemia (AML) developed 6, 6, 5, 13, and 24 months after diagnosis; the patients subsequently died. Three patients died at 1, 1, and 8 months without progression to AML, and only 1 was alive at 10 months.
MDSs with fewer than 5% blasts and Auer rods seem to be a heterogeneous group, but rapid progression to death or AML in most cases suggests that Auer rods signify an aggressive biology in MDSs with a low blast count.
IMMUNO-HISTOCHEMISTRY CHARACTERIZATION CD99
- Immunoreactivity of MIC2 (CD99) and terminal deoxynucleotidyl transferase in bone marrow clot and core specimens of acute myeloid leukemias and myelodysplastic syndromes.
Kang LC, Dunphy CH.
Division of Hematopathology, Department of Pathology and Laboratory Medicine, University of North Carolina, Chapel Hill, NC 27599-7525, USA.
Arch Pathol Lab Med. 2006 Feb;130(2):153-7. Abstract quote
CONTEXT: MIC2 ("thymus leukemia") antigen has been shown to be expressed by T cells and monocytes, as well as B cells and granulocyte-lineage cells. It is most intensely expressed by the most immature thymus T-lineage cells and is more intensely expressed by CD34-positive/CD33-positive myeloid cells (compared to more mature myeloid cells) and the earliest CD34-positive/CD10-positive B-cell precursor cells (compared to cells of later B-cell precursor stages). CD99 (MIC2) is characteristically expressed in precursor B- and T-cell lymphoblastic lymphomas/leukemias, as well as in Ewing sarcoma/primitive neuroectodermal tumors (ES/PNET). It has also been shown to be expressed in a few terminal deoxynucleotidyl transferase (TdT)-positive myeloid processes, but has been uniformly negative in TdT-negative myeloid processes. A more recent study showed that 43% of acute myeloid leukemias (AMLs) and 55% of chloromas express CD99, concluding that CD99 is commonly expressed in AML and rarely seen in myeloproliferative disorders, myelodysplastic syndromes, or normal bone marrow. Although this study speculated that MIC2 expression was probably not limited to TdT-positive AML, there was no comparison with TdT reactivity in this study.
OBJECTIVE: Since AML and high-grade myelodysplastic syndrome may occasionally be difficult to distinguish morphologically from acute lymphoblastic leukemia and ES/ PNET, we undertook a study to analyze MIC2 expression in conjunction with TdT reactivity in distinguishing AML or high-grade myelodysplastic syndrome from acute lymphoblastic leukemia and ES/PNET.
DESIGN: We studied bone marrow core and clot paraffin specimens from AML (classified according to criteria of the World Health Organization; n = 49), myelodysplastic syndromes (n = 4), precursor B-cell acute lymphoblastic leukemia (n = 4), ES/PNET (n = 1), and normal bone marrow (n = 3) with MIC2 (CD99) and TdT immunohistochemistry.
RESULTS: Overall, CD99 was expressed in 24 (49%) of 49 AML cases, including all (11/11) TdT-positive cases. CD99 was expressed in all subtypes of AML except M5. Myelodysplastic syndromes and normal bone marrow specimens were uniformly CD99 negative. Expression of TdT was limited to a subset of AML-M0, -M1, -M2, and -M4, and AML with multilineage dysplasia.
CONCLUSIONS: In contrast to a previous study, CD99 expression was not restricted to TdT-positive hematologic proliferations. In particular, the CD99-positive M3 and M7 AMLs were TdT negative. An M5 AML may likely be excluded based on a uniform TdT-negative/CD99-negative immunophenotype. In addition, in our experience, CD99 should be routinely evaluated on bone marrow clots, owing to decreased reactivity or loss of reactivity in rapid decalcifying (RDO) solution-decalcified specimens.
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Abnormal localization of immature precursors (ALIP)-Immature myeloid cells present in positions different from usual locations of paratrabecular or perivascular-three or more are associated with increased incidence of leukemic evolution.
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