Vulvar and Oral Lesions in a 34-Year Old Woman

Beverly J. Brent, MT(ASCP)BB; Meenakshi Nandedkar, CDR, MC, USNR


Lab Med. 2005;36(10):644-646. 

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  1. The most striking clinical findings were fever and recurrent oral/vulvar lesions. The most striking laboratory findings included marked leukopenia, pancytopenia; markedly increased ESR; peripheral blood smear findings of an excessive number of blast cells, thrombocytopenia, some hypogranular and agranular platelets, and normocytic-normochromic anemia ( Table 1 ) (Figure 1A); and, a hypercellular bone marrow with obliterative vasculitis and an increased number of immature/undifferentiated cells and markedly decreased erythroid cells ( Table 2 ) (Figure 1B).

  2. Our patient's clinical and laboratory findings suggest a non-specific necrotizing inflammatory disorder such as Behcet's syndrome or a hematologic disorder such as refractory anemia with excess blasts (RAEB). The patient's peripheral blood smear (eg, pancytopenia) and bone marrow findings, especially obliterative vaculitis, favors a diagnosis of RAEB. Vasculitis may develop before or after a hematologic disorder and its etiology is unknown.[1] One hypothesis on how vaculitis may develop involves activation of B cells and the synthesis of organ-specific and non-organ specific autoantibodies. Another hypothesis involves severely impaired macrophage function which results in decreased clearance of immune complexes, neutrophil chemotaxis, and organ injury from increased superoxide anion production. Another hypothesis suggests that changes in the bone marrow play a significant role in the etiology of vasculitis. To distinguish between Behcet's syndrome and RAEB as the cause of our patient's laboratory findings, correlation of laboratory findings with clinical findings was required because pancytopenia is not a typical feature of Behcet's syndrome; however, this syndrome has been associated with clonal myeloid disorders. Behcet's syndrome (or disease) is a rare complication of myelodsyplastic syndrome (MDS) with only 10 cases having been reported up to 1997.[2] Behcet's syndrome is characterized by recurrent oral/genital ulcers and eye/skin lesions. The tissue injury that occurs in patients with this syndrome is caused by excessive production of reactive oxygen species (ROS) by activated neutrophils. On the other hand, patients with MDS are usually characterized by decreased production of ROS. Moreover, when Behcet's disease is associated with MDS, trisomy 8 is the most common karyotypic abnormality observed, involving 8.9% to 18.4% of patients with MDS-associated Behcet's syndrome.[2] Trisomy 8 occurs in MDS patients more frequently than in patients with Behcet's disease. The findings by Ohno and colleagues suggest that this chromosomal abnormality may predispose a subgroup of MDS patients with trisomy 8 to Behcet's disease.[2] In the majority of patients studied by this group of investigators, Behcet's disease occurred after the onset of MDS. In addition, increased concentrations of cytokines and growth factors were found in serum from these patients prior to the onset of Behcet's disease. It has been suggested that Trisomy 8 may contribute to the pathogenicity of MDS-associated Behcet's syndrome by producing such serum factors as granulocyte-colony stimulating factor (G-CSF), tumor-necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), and IL-8.[2] Lastly, anemia, thrombocytopenia, and peripheral blood smear findings consistent with excess immature white blood cells rarely occur in patients with Behcet's disease. Therefore, when these findings occur, clinicians should consider MDS with Trisomy 8 as a possible diagnosis.

  3. Most likely diagnosis: refractory anemia with excess blasts (RAEB). Most patients with RAEB are older than 50 years of age and males and females are affected equally. In addition, this syndrome evolves into AML in about 30% to 50% of cases.

  4. Additional testing to confirm the diagnosis of RAEB and identify its subtype should include morphologic analysis of stained bone marrow and reticulum smears, using Wright-Giemsa, hematoxylin-eosin (H&E) and iron stains; flow cytometry using lymphoma/leukemia cell markers; and cytogenetics. In addition, measurement of serum iron, vitamin B12, and folic acid levels is useful in identifying the anemia as refractory, if the patient is not responsive to therapy to reverse the anemia.[1] Our patient's bone marrow demonstrated decreased erythroid cells with scanty, stainable iron content consistent with a normocytic-normochromic anemia ( Table 2 ) (Figure 1B). Flow cytometry findings were consistent with a clonal proliferation of myeloid cells resulting in impaired hematopoiesis, consistent with acute myeloid leukemia (AML) ( Table 2 ) (P=0.1, log-rank test). Cytogenetic findings, including fluorescence in situ hybridization (FISH) analysis for the core binding factor-β (CBFB) rearrangement, [inv(16) or t(16;16)], indicated a normal karyotype and no CBFB rearrangement.

  5. Patients with MDS demonstrate significant clinical variability.[3] The French-American-British (FAB) classification criteria for MDS include <30% blasts in the bone marrow and peripheral blood with evidence of ineffective hematopoiesis.[3] The World Health Organization (WHO; 2001 guidelines) classification critiera for MDS indicate 20% blasts in the peripheral blood or bone marrow as consistent with a diagnosis of AML. Moreover, WHO provides criteria for subtyping RAEB based on the percentage of peripheral blood and bone marrow blast cells. Patients with <5% peripheral blood blast cells and 5% to 9% bone marrow blast cells are classified as RAEB-1, while those with 5% to 19% peripheral blast cells and 10% to 19% bone marrow blast cells are classified as RAEB-2.[4] Moreover, Albitar and colleagues reported that the similarity in outcome data for patients with AML and MDS does not necessarily imply that these diseases are biologically similar because there is significant overlap when these 2 diseases are distinguished based on the percentage of peripheral blood and bone marrow blast cells.[3] Their data suggests that a classification scheme based on the biology of MDS is needed. Strupp and colleagues analyzed the subtypes of RAEB according to the FAB classification criteria: hematological characteristics, karyotype anomalies, and prognosis.[5] Their findings supported the elimination of Auer rods as a criterion for classification of RAEB using the new WHO classification scheme. Lastly, there is concern among hematopathologists that patients classified previously as RAEB-t (refractory anemia with excess blasts in transformation) using the FAB classification scheme based on a peripheral blood blast count of at least 5% are now reclassified as RAEB-2. The concern stems from the fact that this feature predicts a median survival similar to that of patients with AML, it does not reflect their unfavorable prognosis, and it increases the prognostic heterogeneity of the RAEB-2 category.

  6. Because of our patient's peripheral blood findings of pancytopenia with leukoerythroblastosis and a blast cell count of 5% and bone marrow hypercellularity (90%), no clonal abnormalities, and trilineal myelodysplasia with 12% blasts, our patient's final diagnosis is RAEB-2. Our patient's normal karotype was not at odds with this interpretation because 52% of patients with MDS lack a karotypic abnormality.

  7. Hypersplenism (HS) due to liver cirrhosis or a hepatoma, aplastic anemia (AA), and myelodysplastic syndrome (MDS) are the most common diseases associated with pancytopenia.

  8. The reticulocyte count is a common diagnostic indicator of erythropoietic activity. Flow cytometry was applied by Kabutomori and colleagues to examine whether the number of total and immature reticulocytes was decreased in blood from patients with HS, AA, or MDS and pancytopenia.[6] Because MDS involves an intrinsic defect in the maturation of hematopoietic cells in the bone marrow, the number of reticulocytes may not increase when the level of erythropoietin increases. They concluded that the number of total and immature reticulocytes was highly decreased in patients with MDS and pancytopenia.[6]

  9. Median survival of patients with RAEB is about 9 months, although there are occasional long-term survivors.[7] Moreover, median survival in patients with RAEB-1 is 18 months and 10 months in patients with RAEB-2. In patients with RAEB, periodic hematologic evaluation of blood and bone marrow is essential to prolonged survival in these patients.

  10. In most cases, the treatment of patients with RAEB should be highly individualized. Most patients with RAEB require treatment for weeks to months. Since the response to cyto-toxic therapy is poor, a concurrent, symptomatic treatment regimen, including blood transfusion and administration of antibiotics as needed, is required. If the disease progresses to AML and the patient can sustain standard therapy for AML, this therapy is utilized in such patients. Moreover, patients with RAEB who are under 50 years of age and have a histocompatible donor should be considered for stem cell transplantation.[7] Patients with MDS and RAEB are at increased risk for progression to AML. In these patients, treatment options are limited because of the refractory nature of their disorder to conventional cyto-reductive chemotherapy.


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