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May-Hegglin anomaly is the presentation of a qualitative platelet disorder characterised by large platelets, thrombocytopenia and granulocyte inclusions as a result of mutations in the MYH9 gene. Though often overlooked given its rarity, it should be considered in patients who present with epistaxis, bruising, menorrhagia and easy bleeding as it can be mistaken for other diagnoses resulting in unnecessary treatments and tests. Our case study reports one presentation of this anomaly and can help broaden awareness of the presentation of this type of patient.

Post-transplant lymphoproliferative disease (PTLD) is a recognized complication following solid organ and stem cell transplants with subsequent immunosuppression and is the most common malignancy complicating solid organ transplantation. Improved survival and use of aggressive immunosuppression following solid organ transplants have led to increased diagnosis of PTLD. Nevertheless, spinal involvement in PTLD is extremely rare. To our knowledge, this is the first report of PTLD causing epidural spinal cord compression of the cervical spine, mimicking the imaging and pathology of an epidural abscess. The patient underwent posterior and subsequent anterior decompression and stabilization. Rarity of occurrence of PTLD in the spine with absence of diagnostic imaging features may preclude differentiating it from the more commonly occurring lesions such as epidural abscess which occurs in a similar clinical setting. As the management strategy and overall prognosis are dramatically different, the importance of considering PTLD in the differential diagnosis for epidural spinal cord compression in a transplant recipient patient cannot be overemphasized.

Introduction Castleman disease (CD) is a benign lymphoproliferative disorder with hyaline vascular (HVCD), plasma cell (PC-CD), and mixed subtypes. Only HVCD lymph node cytomorphology has been described, mainly as case reports. We reviewed all CD subtypes. To the best of our knowledge, our case series is the largest and most comprehensive yet published. Materials and methods We searched our institution's database for histologically confirmed CD cytology cases (fine needle aspiration, touch preps) for the past 23 years. Two independent pathologists evaluated cytomorphology. We then reviewed touch preps from 6 histologically confirmed, non-CD reactive lymph node excisions. Results 8 patients (5 women, 3 men) had the following subtypes: HVCD (5 patients), PC-CD (2), and mixed (1). All cases had a heterogenous background population composed predominantly of small lymphocytes with single and clustered follicular dendritic cells (FDCs). The FDCs had delicate pale cytoplasm with indistinct borders showing lymphocyte emperipolesis. They were often binucleated or multinucleated with fine chromatin, regular nuclear borders, large nuclei, and small nucleoli. HVCD cases had traversing, frequently hyalinized capillaries. PC-CD cases had increased plasma cells, including binucleate forms, and tingible body macrophages with fewer FDC clusters. Human herpes virus-8 immunostain was negative in all cases. Non-specific follicular hyperplasia cases had abundant tingible body macrophages, rare hyalinized capillaries, and no lymphocyte emperipolesis. Conclusions CD is distinguished by background lymphocytes and cohesive FDC clusters with lymphocyte emperipolesis. HVCD has traversing, hyalinized capillaries and PC-CD has increased plasma cells and tingible body macrophages. Knowledge of these features can prevent a lymphoma misdiagnosis.

The majority of chronic myelomonocytic leukemia (CMML) cases arise de novo; cases evolving from preexisting myelodysplasia (MDS) or myeloproliferative diseases have not been well-studied. We conducted the present study to determine the clinicopathologic features and to study possible underlying molecular and cytogenetic mechanisms involved in this evolution. Between April 1995 and November 2005, we identified 120 CMML cases, of which 20 (16.7%) had a previous diagnosis of MDS. Of the 20 patients with MDS, 6 had relative monocytosis at diagnosis. At the time of MDS to CMML evolution, mutations in JAK2 (V617F), FLT3 (ITD), K-ras-2, or N-ras were not acquired, and only 1 (6%) of 17 evaluable cases showed cytogenetic progression. The median time to evolution from MDS to CMML was 29 months, and the median survival following CMML development was 13 months. Three cases (17%) transformed to acute myeloid leukemia. These findings indicate that in some cases of otherwise typical MDS, the progenitor cells may have some capacity for monocytic proliferation at diagnosis and manifest rapid disease progression once a monocytic proliferation supervenes.

Refractory anemia with ringed sideroblasts associated with marked thrombocytosis harbors JAK2 mutation and shows overlapping myeloproliferative and myelodysplastic features

An acquired form of sideroblastic anemia has been described in association with several drugs, especially anti-microbial agents. A case of sideroblastic anemia is presented in a patient with a left ventricular assist device drive-line infection who was receiving linezolid, an antibiotic used for serious infections with gram-positive organisms. This patient's anemia resolved after discontinuation of the drug; he subsequently underwent an uncomplicated orthotopic heart transplant with no recurrence of anemia. As linezolid has been shown to have hematologic side effects, blood count monitoring is recommended in patients receiving this drug for long-term therapy.

Twenty patients with poor prognosis AML and four patients in the blastic phase of a myeloproliferative disorder were treated with two 'pulses' of therapy each consisting of two doses of high dose araC (separated by 12 h) followed by a single dose of mitoxantrone. The pulses were separated by 96 h. Amifostine was then administered tiw. The median age of the population was 68 years with 88% of patients having had either a prior MDS, MPD or toxic exposure. The acute leukemia of 58% of patients either entered a CR or reverted to preleukemic state. For patients under 70 years of age, treatment produced 62% CRs with a leukemia free decision marrow in 77%. For patients over 70 years the CR rate was 27% with 36% of patients having a leukemia free decision marrow.

Rates of proliferation and apoptosis as well as expression of tumor necrosis factor alpha (TNF-alpha), transforming growth factor beta (TGF-beta) and the number of macrophages were measured in bone marrow (BM) biopsies of 33 patients who presented with hypocellular (cellularity30%) myelodysplastic syndromes (MDS). Results showed that 2/3 of the patients had high apoptosis, high cytokine levels and large number of macrophages in their biopsies while 1/3 did not. Apoptosis and TNF-alpha levels were directly related (r = 0.583, P = 0.003, n = 24) as was apoptosis and the degree of anemia (P = 0.033, n = 18). A subgroup of patients with abnormalities of chromosomes 5 or 7 had higher platelets (P = 0.026) and higher apoptosis (P = 0.038) when compared with the rest of the group. Eight patients had no evidence of apoptosis and almost no detectable TNF-alpha in their biopsies. We conclude that within the hypocellular variant of MDS, there may be two distinct sub-groups of patients, one who present with high cytokine-mediated intramedullary apoptosis and the other who may be better characterized as having a stem-cell failure defect since they showed no evidence of apoptosis.

A comparison was made of the cytokine transcripts in normal, monoclonal, MDS, and AML marrow aspirates. While both normal and monoclonal marrow aspirates contain transcripts for SCF, few MDS or AML marrow aspirates contain these transcripts. Similarly, IL1ra transcripts are found with reduced frequency in MDS and AML marrow aspirates. The fall in SCF transcripts between monoclonal and MDS marrow aspirates parallels the appearance of apoptosis and the reduced in vitro proliferative ability which are characteristics of MDS marrow aspirate cells. The frequent IL1beta production by MDS and AML marrow aspirate cells, with few marrow aspirates producing IL1ra transcripts, suggests that unbalanced IL1beta effects may contribute to the proliferative advantage of MDS and AML cells over their normal counterparts.

We describe a case of recurrent Kikuchi's disease in a South Asian-American man that was treated successfully with chloroquine and on recurrence with hydroxychloroquine. Each treatment led to a very prompt response.

We describe a novel double-labeling method to simultaneously investigate proliferation and apoptosis from plastic-embedded biopsy specimens (PEBs). Infusions of bromo- and/or iododeoxyuridine (BrdU/IudR) were given to 10 patients, five with acute myeloid leukemia (AML) and five with myelodysplastic syndromes (MDS), and S-phase cells were measured in PEBs using a monoclonal anti-IudR/BrdU antibody. Apoptosis was measured by in situ end-labeling (ISEL) of DNA. The results demonstrate that both AML and MDS are highly proliferative disorders but that there is almost no apoptosis in the former, whereas extensive apoptosis was observed in the latter. Double labeling revealed that large numbers of S-phase cells in MDS were simultaneously undergoing apoptosis. We conclude that the high cell death in MDS cancels the high cell birth, resulting in a functionally aplastic marrow and thus accounting for the observed ineffective hematopoiesis. On the other hand, AML is rapidly fatal, probably owing to high cell birth with no or minimal cell death. Therapeutic strategies to prevent intramedullary programmed cell death of hematopoietic precursors should be evaluated in MDS, and efficacy of chemotherapy in AML can be assessed by measuring the induction of apoptosis in post-treatment biopsy specimens.

We report the fine-needle aspiration (FNA) cytology findings of Subcutaneous Panniculitis-like T-cell Lymphoma (SCPTCL) in a 66-year-old woman who presented with a four month history of asymptomatic subcutaneous nodules on her right chest wall and back. An excisional biopsy of the right chest nodules was performed, and the diagnosis of SCPTCL was rendered. On a follow-up visit, several skin lesions were noted throughout her body. A fine-needle aspiration (FNA) of the right inguinal region was performed. The FNA yielded cellular smears, composed mainly of sheets of epithelioid histiocytes and scattered multinucleated cells. However, no distinct granulomas were noted. The background of the cytological smears showed scattered atypical lymphoid cells, some of which displayed nuclear membrane irregularities. To the best of our knowledge, the cytological features on FNA material of SCPTCL have not been described.

In the last two decades posttransplant lymphoproliferative disorders (PTLDs) have been recognized as a complication of organ transplantation with immunosuppression. The reported incidence of PTLDs in renal transplant patients ranges between 0.3–3% (Birkeland et al., Transplantation 1999;67:876–881). In contrast to the reported incidence of PTLDs in post bone marrow transplant, it is 1% in HLA-matched recipients and up to 20% in HLA mismatched T-cell depleted bone marrow recipients (Curtis et al., Blood 1996;94:2208–2216).2 In cardiac transplant recipients the reported incidence of PTLDs is between 1.8–9.8 (Mihalov et al., Clin Transplant 1996;10:248–255). PTLDs are predominately extranodal. They have varied morphologic patterns and clonality, but almost all are associated with Epstein-Barr virus (EBV). The vast majority are of B cell lineage; only about 10% are of T-cell origin. We report a T-cell anaplastic large cell lymphoma (ALCL) presenting with bilateral pleural effusion and liver involvement in a renal transplant recipient. Diagn. Cytopathol. 2002;27:35–37. © 2002 Wiley-Liss, Inc.

Thalidomide was administered to 83 patients with myelodysplastic syndrome (MDS), starting at 100 mg by mouth daily and increasing to 400 mg as tolerated. Thirty-two patients stopped therapy before 12 weeks (minimum period for response evaluation), and 51 completed 12 weeks of therapy. International Working Group response criteria for MDS were used to evaluate responses. Intent-to-treat (ITT) analysis classified all off-study patients as nonresponders. Off-study patients belonged to a higher risk category (P =.002) and had a higher percentage of blasts in their pretherapy bone marrow than patients who completed 12 weeks of therapy (P =.003). No cytogenetic or complete responses were seen, but 16 patients showed hematologic improvement, with 10 previously transfusion-dependent patients becoming transfusion independent. Responders had lower pretherapy blasts (P =.016), a lower duration of pretherapy platelet transfusions (P =.013), and higher pretherapy platelets (P =.003). Among responders, 9 had refractory anemia (RA); 5 had RA with ringed sideroblasts; and 2 had RA with excess blasts. By ITT analysis, 19% of patients (16 of 83) responded, and when only evaluable patients were analyzed, 31% (16 of 51) responded. It was concluded that thalidomide, as a single agent, is effective in improving cytopenias of some MDS patients, especially those who present without excess blasts. (Blood. 2001;98:958-965)

The proliferation of acute myelogenous leukemia cells is dependent upon cytokine stimulation. Additionally, there is a body of literature which reports that leukemia cells produce GMCSF, IL6, and other cytokines. The study reported here, using an rt-multiplex polymerase method, determined the presence or absence of transcripts in freshly obtained AML cells for the following cytokine or cytokine-related genes: IL 1b, IL1ra, TNFa, GMCSF, IL6, flt 3, and hSCF. This demonstrated that leukemia cell populations usually contain transcripts for IL1b, TNFa, flt 3 and flt 3 ligand in vivo and that transcripts for the other cytokines only appear after the leukemia cells are processed in vitro. The presence of TNFa transcripts appears to be associated with resistance to remission induction therapy. Furthermore, the transcript profile of the leukemia cells can change during remission induction therapy. The data also demonstrate the assessment of cytokine production by leukemia cells after in vitro manipulation should not be extrapolated to the in vivo situation. © 1998 Elsevier Science Ltd. All rights reserved.

Forty-three patients with myelodysplastic syndromes (MDS) were treated with a combination of pentoxifylline and ciprofloxacin (PC) with the addition of dexamethasone (PCD) in 18 patients who failed to respond to PC. There were 15 females and 28 males, and the median age was 67 years. A total of 18 patients either showed a hematopoietic improvement, a partial or complete cytogenetic response or a combination of both for an overall response rate of 42%. Seven PC only patients responded, four showing hematologic improvement, two cytogenetic responses and one patient showing a combined response. This 16% response rate to PC was increased to 61% by the addition of dexamethasone with 11/18 patients showing a response. Four of the 7 patients who responded initially to PC were given dexamethasone after at least 12 weeks of PC therapy, and only 1 showed a further improvement in response. Thus, we conclude that the combination of PCD provides an encouraging novel approach to treating MDS. The mechanism of action is probably related to the suppression of a veriety of cytokines which in turn attenuate the excessive intramedullary apoptotic death of hematopoetic cells in MDS, an observation which has been speculated to be the basis of the paradox of variable cytopenias despite cellular marrows in MDS. Larger numbers of patients need to be treated and followed for longer periods to determine the true efficacy of this therapy, especially the nature and duration of the cytogenetic responses.

The secondary hematologic disorders consist of the progressive appearance of increasingly abnormal marrow cell populations with increasingly abnormal hemopoiesis culminating in the appearance of secondary acute myelogenous leukemia. At the biological level the secondary hematologic disorders result from the accumulation of molecular genetic lesions which confer a proliferative advantage on a stem cell and its progeny which in turn results in the successive overgrowth of increasingly abnormal monoclonal cell populations. We have identified 4 of 15 female patients cured of lymphoma by intensive cytotoxic therapy as having monoclonal hemopoiesis. Despite the presence of normal peripheral blood counts, the bone marrows of the 3 patients who were studied intensively manifested evidence of grossly abnormal hemopoiesis. We have named this state of normal blood counts in combination with monoclonal hemopoiesis in patients previously exposed to hemopoietic toxins “preMDS.” This “preMDS” state either represents an earlier stage of the secondary hematologic disorders or represents a transient preclinical manifestation of myelodysplasia. Longitudinal patient follow up is needed to distinguish between these two possibilities.

The study was carried out on 22 patients with non-Hodgkin's lymphoma (NHL) who had received sequential infusions of two thymidine analogues iododeoxyuridine (IUdR) and bromodeoxyuridine (BrdU). Cell cycle kinetic studies seemed to differentiate distinctly between low grade lymphoma (n = 8, LI = 2.6%) compared to that of intermediate grade (n = 9, LI = 13%, p = 0.0001) and high grade NHL (n = 5, LI = 16.3%, p = 0.0062). While the majority of 14 intermediate and high grade lymphomas had a high labeling index there were 3/14 patients with a LI of 5.5%, 5.5% and 4.1% respectively. A decrease in the rate of programmed cell death (PCD) or apoptosis due to the overexpression of bcl-2 has been implicated as the possible pathogenesis for follicular lymphoma. We determined the presence of bcl-2 protein immunohistochemically and apoptosis by in situ end labeling of DNA which detects cells in early stages of PCD not recognized morphologically. Nine NHL patients demonstrated PCD ranging from 1%-40%, while it was undetectable in 13/22 patients. Of these 13 cases, 6 showed the presence of bcl-2 expression. To understand the relationship of the microenvironment to the lymphoma cells, the presence of transforming growth factor beta (TGF-beta) was determined immunohistochemically. TGF-beta was present in all the cases where bcl-2 was present, except one. This study highlights some of the key biological features of NHL cells and their microenvironment.

Despite hypercellular bone marrows (BM), peripheral cytopenias are the rule in patients with myelodysplastic syndromes (MDS). This study examined the roles played by cell birth and cell death rates in generating this paradox. Cell kinetics from BM biopsies of 35 MDS patients were measured using intravenous infusions of either iododeoxyuridine or bromodeoxyuridine, or both. Degree of apoptosis or programmed cell death (PCD) was estimated using in situ end-labeling of DNA directly from BM biopsies, which were simultaneously double-labeled for proliferation/PCD. MDS were found to be highly proliferative disorders with large numbers of myeloid, erythroid, and megakaryocytic cells synthesizing DNA. Median cycling time (Tc) of myeloblasts was more rapid than that of patients with acute myeloid leukemia (44.1 hr vs. 56.0 hr). Interestingly, most marrow cells of all three lineages in 32 of 34 evaluable cases were undergoing PCD. In 19 of 32 patients, greater than 75% cells were apoptotic. Surprisingly, large numbers of S-phase cells were found to be simultaneously undergoing PCD, as were stromal cells of the BM microenvironment. We conclude that the extensive apoptosis in hematopoietic cells effectively cancels the high birth rate resulting in ineffective hematopoiesis and accounting for deficient bone marrow function. ©1995 Wiley-Liss, Inc.

Background: The Myelodysplastic syndromes (MDS) are hematopoietic stem cell disorders, characterized by cytopenia, and risk of progression to acute leukemia. Chromosomal abnormalities are detected in 40–60%of patients with MDS. Cytogenetic findings are critical for diagnosis, prognosis and monitoring therapy. FISH has been reported to detect occult clonal abnormalities in 15–7.8% of karotypically normal patients in some studies, but found to be of limited value in others. We sought to evaluate whether FISH can be a valuable diagnostic/prognostic adjunct to conventional cytogenetic (CC) analysis. Methods: Since the implementation of FISH panel at our institution, we have identified 62 MDS patients who had both CC and FISH panel tests performed simultaneously. Our FISH panel was designed specifically to detect abnormalities in chromosomes 5, 7, 8, 11 and 20. Results: In these patients, concordance between the 2 methods was noted in 43 patients (69.3%). Clonal chromosomal abnormalities were detected by CC in 36 patients (58 %). FISH defined additional clones in 7/26 patients with normal and 3/36 patients with an abnormal karyotype increasing the detection rate by 16%. Importantly, 9/36 patients with abnormal CC had clonal abnormalities in chromosome regions not analyzed, thus not detected, by our FISH panel. To further evaluate the prognostic significance of the additional clones detected by FISH, we calculated and compared the IPSS risk category for the 10 patients identified with discordant results utilizing data derived from CC and FISH. 3 patients had no change in their IPSS scores, 7 patients had an upgrade in their IPSS scores as follows: from low to Int-1: 4, Int-1 to Int-2: 2, and Int-2 to High: 1. If one were to apply NCCN guidelines with regard to treatment options according to IPSS risk categories, FISH upgraded scores could potentially result in change of therapy in 2/10 patients with discrepancy, and in 2/62 (3%) patients altogether. Conclusion: Our results suggest that FISH has the potential of increasing the rate of detecting chromosomal abnormalities in complete CC studies that have failed to reveal clonal abnormalities. However, the practical impact of finding such clones seems to be very low resulting in potential change of clinical management in only 3% of patients. Furthermore, in cases with identified cytogenetic abnormalities, FISH was of limited benefit. Our series is small and retrospective in nature; prospective studies addressing the utility, benefit, and cost justification of this method are needed.

The paradox of myelodysplastic syndromes (MDS) which present with pancytopenias despite cellular bone marrows (BM) was investigated by conducting detailed studies of proliferation and apoptosis in 89 MDS patients. Our results demonstrated a rapid rate of both proliferation as well as apoptosis. Levels of three cytokines, tumor necrosis factor-alpha (TNF-alpha), transforming growth factor-beta (TGF-beta) and interleukin-1 beta (IL-1 beta) were measured in the same patients. High levels of TNF-alpha were found to correlate with high levels of apoptosis in 83 MDS patients (P = 0.0045). We propose a dual role for TNF-alpha (or other cytokines) in the pathogenesis of MDS. On the one hand, TNF-alpha induces apoptosis in the maturing cells causing pancytopenia while on the other, it stimulates the proliferation of the primitive progenitors accounting for the hypercellular BM frequently seen in MDS. A new model for MDS is presented. The initial abnormality probably affects a primitive hemopoietic progenitor which acquires a growth advantage leading to monoclonal hemopoiesis, which in turn makes these cells susceptible towards acquiring additional mutations and appearance of cytogenetically marked (or unmarked) clones. Cytokines such as TNF-alpha whose source is presently unknown, then contribute towards the clinical syndrome of pancytopenia and hypercellularity.

The present report describes the neuropathological change found in the brainstem of four patients who were treated with combined chemotherapy for various types of malignant disease. The change consists of localized axonal swellings, the so-called "axonal spheroids" located predominantly in the medial lemniscus, the fibers from the olivary nuclei and around some of the cranial nerve nuclei. In addition to the brain change, all four patients had shown histological evidence of hepatic injury, although none of the patients exhibited overt clinical or chemical evidence of hepatic insufficiency. Neither did these patients show any clinical neurological deficit that could be related to the pathological findings. The neuroaxonal changes are most likely the result of altered metabolism as a consequence of the chemotherapy.

Twenty-five patients with a diagnosis of myelodysplastic syndromes (MDS) were randomized to either begin therapy with pentoxifylline, ciprofloxacin and dexamethasone (PCD) immediately (10 patients) or after a 12 week observation period (control arm, 15 patients). PCD was administered with the goal of suppressing cytokine-induced excessive intramedullary apoptosis of hematopoietic cells. No marked fluctuations of blood counts were noted during the period of observation. Twenty-two patients completed at least 12 weeks of therapy: 18/22 showed some type of hematologic response, 9/18 showing an improvement in absolute neutrophil count only (p =0.001) and 9/18 showing multi-lineage responses. No unique category of MDS responded better, however 19/25 patients had refractory anemia (RA)/RA with ringed sideroblasts. The median time to response was 6 weeks and 3/18 responding patients maintained their responses beyond a year. We conclude that hematologic improvement in response to PCD therapy supports the validity of this unique anti-cytokine approach. Future trials should combine PCD therapy with established approaches (growth factors/chemotherapy) and also should focus on identifying more effective ways of suppressing the pro-apoptotic cytokines in MDS.