Cerebral spinal fluid involvement by Hodgkin's disease diagnosed by CSF cytology and immunocytochemistry

A 39-yr-old man with stage IV Hodgkin's disease (HD) involving bone marrow was being evaluated for autologous bone marrow transplantation when he developed diplopia, prompting a lumbar puncture tap for cerebral spinal fluid (CSF) examination. Cytologic examination of the CSF revealed numerous Reed-Sternberg (RS) cells in a polymorphous inflammatory background of small lymphocytes, monocytes, rare plasma cells, and eosinophils. However, magnetic resonance imaging (MRI) studies of the brain and spinal cord failed to reveal evidence of leptomeningeal disease or intracranial masses. Repeat CSF examination again demonstrated cytologic evidence of HD. Immunocytochemical stains established that the RS cells and mononuclear Hodgkin's cells were positive for CD30 and CD20 but negative for CD15; this phenotype was identical to that of RS cells in the initial diagnostic bone marrow biopsy, confirming CSF involvement by HD. The patient was treated with intrathecal methotrexate, 15 mg, 6 days after his bone marrow transplant. After treatment, all subsequent CSF cytology specimens were negative for tumor. In this case of disseminated HD, cytologic examination allowed for early detection of CNS involvement by lymphoma prior to development of radiographically detectable lesions.     

37-year-old woman with multiple intracranial masses

Extramedullary hematopoiesis (EMH), defined as the presence of hematopoiesis outside bone marrow and peripheral blood, occurs asa compensatory phenomenon in several hematologic disorders and bone marrow dysfunction. EMH predominantly affects reticuloendothelial system including the spleen, liver and lymph nodes. Here,we report a rare case of multiple intracranial meningeal EMH. A37-year-old woman was anemic with gradually worsening vision for 8 months. Multiple extra-axial masses were found on imaging and the patient underwent the biopsy for the left frontotemporal lesion.Final diagnosis was multiple intracranial meningeal EMH. Treatment of fractionated external beam radiotherapy resulted in marked symptomatic improvement. This case indicates that although the diagnosis of meningeal EMH is difficult, there is a need to consider EMHin the differential diagnosis of anemic patients with tumor-like mass lesions in extramedullary sites.     

Endoscopic ultrasound guided fine‐needle aspiration of a splenic hemangioma with extramedullary hematopoiesis

Extramedullary hematopoiesis (EMH) is the production of mature blood elements outside of the bone marrow and can occur as a compensatory result of a marrow replacing process or from marrow space occupying lesions such as tumor or marrow fibrosis. EMH can also be induced by factors elicited by neoplasms, such as vascular endothelial growth factor (VEGF). Usually, EMH is a diffuse process most commonly observed in lymph nodes, liver, and spleen. Rarely, EMH can form a mass lesion. Although the spleen is a common site for diffuse EMH, it is a rare location for a mass forming EMH. Hemangiomas are the most common benign tumors of the spleen. A case of a discrete, 8 cm lesion was noted incidentally on CT scan in a 59‐year‐old man with no significant past medical history. Endoscopic ultrasound guided fine‐needle aspiration (EUS FNA) biopsy was performed and cytologic examination revealed trilinear hematopoiesis, with the most distinctive elements being megakaryocytes and erythroid precursors. A diagnosis of EMH was made. On resection, the mass was a hemangioma with EMH. EUS guided FNA is a useful tool for diagnosing splenic masses. Awareness of EMH, both as a mass forming lesion and a feature associated with benign and malignant vascular lesions is important, especially in patients with hematologic malignancies or marrow replacing processes. Diagn. Cytopathol. 2013;41:1086–1090. © 2011 Wiley Periodicals, Inc.     

Chronic idiopathic myelofibrosis presenting as cauda equina compression due to extramedullary hematopoiesis: a case report

Extramedullary hematopoiesis (EMH) is occasionally reported in idiopathic myelofibrosis and is generally found in the liver, spleen, and lymph nodes several years after diagnosis. Myelofibrosis presenting as spinal cord compression, resulting from EMH tissue is very rare. A 39-yr-old man presented with back pain, subjective weakness and numbness in both legs. Sagittal magnetic resonance imaging showed multiple anterior epidural mass extending from L4 to S1 with compression of cauda equina and nerve root. The patient underwent gross total removal of the mass via L4, 5, and S1 laminectomy. Histological analysis showed islands of myelopoietic cells surrounded by fatty tissue, consistent with EMH, and bone marrow biopsy performed after surgery revealed hypercellular marrow and megakaryocytic hyperplasia and focal fibrosis. The final diagnosis was chronic idiopathic myelofibrosis leading to EMH in the lumbar spinal canal. Since there were no abnormal hematological findings except mild myelofibrosis, additional treatment such as radiothepary was not administered postoperatively for fear of radiotoxicity. On 6 month follow- up examination, the patient remained clinically stable without recurrence. This is the first case of chronic idiopathic myelofibrosis due to EMH tissue in the lumbar spinal canal in Korea.     

Pleural fluid extramedullary hematopoiesis case report with review of the literature

Extramedullary hematopoiesis (EMH) is the trilineage formation of normal blood cells outside of the bone marrow. While predominantly seen in the spleen and liver, EMH rarely occurs in serous effusions. Accurate diagnosis requires recognition of megakaryocytes and other precursor hematopoietic elements. We present a case of pleural fluid EMH in a patient with primary myelofibrosis and developing leukemia, with a review of the literature, prognostic implications and diagnostic challenges. Diagn. Cytopathol. 2016;44:41–44. © 2015 Wiley Periodicals, Inc.     

Bone marrow findings in systemic mastocytosis

The neoplastic proliferation of tissue mast cells constitutes a group of rare diseases that have localized and systemic variants. The cytologic (n = 7) and histologic (n = 38) findings in bone marrow from a total of 45 patients with systemic mastocytosis were evaluated. Three distinct histologic patterns of marrow involvement were distinguished. In 21 cases a patchy or focal infiltration pattern was encountered. Mast cell aggregates were located predominantly in peritrabecular and perivascular areas. The adjacent trabeculae were thickened. A dense network of reticulin fibers and foci of lymphocytes accompanied the mast cell infiltrates. Increased numbers of eosinophils frequently demarcated the mast cell infiltrates from the surrounding tissue. In the noninfiltrated marrow areas hematopoiesis and the distribution of fat cells appeared to be normal. This histologic pattern, designated type 1, was observed exclusively in patients showing primary involvement of the skin, indistinguishable from urticaria pigmentosa. In 14 additional cases peritrabecular and perivascular sheets of mast cells, with concomitant fibrosis and osteosclerosis, were also present. Unlike the findings in type 1, however, the noninfiltrated marrow areas showed marked reductions in fat cell content and markedly increased granulocytopoiesis or increased numbers of blast cells (infiltration pattern type 2). On the basis of the hematologic and clinical findings, chronic myeloid leukemia was diagnosed in six of these cases, myelomonocytic leukemia in three cases, and acute myeloid leukemia in two cases. The bone marrow of three patients was diffusely infiltrated by atypical mast cells, leading to marked hypoplasia of fat cells and blood cell precursors. These histologic features were identified as infiltration pattern type 3. The diagnosis of mast cell leukemia was confirmed in all three cases by the presence of numerous mast cells in the blood. The prognosis for patients with the type 1 marrow infiltration pattern and primary skin involvement was favorable (actuarial survival rate five years after diagnosis, 0.75). This variant was called benign systemic mastocytosis. Primary skin involvement did not occur in the patients with type 2 or 3 infiltration patterns. The prognosis for these patients was poor (actuarial survival five years after diagnosis, 0.17 for type 2 and 0.00 for type 3). These two forms were accordingly designated malignant systemic mastocytosis.     

Blastic transformation of essential thrombocythemia. A case report

A case of blastic transformation of essential thrombocythemia (ET) is reported. A 69-year-old male was first admitted to hospital because of fever in February, 1982. He was diagnosed as having ET because of marked thrombocytosis (205.5 x 10(10)/1), absence of erythrocytosis, absence of splenomegaly, normal karyotype and no increment of blasts in the bone marrow, and normal levels of neutrophil alkaline phosphatase, vitamin B12 and folate. He was treated with busulfan, and subsequently his platelet count was well controlled for about five years. At the second admission, blasts were present in the peripheral blood, and later accounted for 49% of the total leukocyte count. Histological examination of a bone biopsy specimen showed homogeneous proliferation of blastic cells and slight reticulin fibrosis. At autopsy, the degree of bone marrow fibrosis had increased. This was considered to be a very rare case of ET with blastic transformation in the terminal phase.     

Intravascular lymphomatosis with bone marrow involvement.

We describe the case of a 56-year-old man who presented with numbness and tingling of the extremities, weakness, and fatigue. Laboratory findings included anemia and thrombocytopenia. A diagnosis of intravascular lymphomatosis was established when liver, omentum, and bone marrow samples were examined. A review of the literature reveals that most cases of intravascular lymphomatosis have cytopenias, mainly anemia and thrombocytopenia, but bone marrow involvement is rare. In our case, a subtle neoplastic infiltrate in the marrow sinusoids was highlighted with a B-cell marker. While immunohistochemical analysis was not performed in most reported cases in the literature, our studies suggest that a systematic search in bone marrow of cases of intravascular lymphomatosis may reveal unsuspected neoplastic cells. We conclude that bone marrow involvement in intravascular lymphomatosis appears to be rare, has subtle features, and is difficult to diagnose if unsuspected and not searched for.     

Adrenal extranodal NK/T‐cell lymphoma diagnosed by fine‐needle aspiration and cerebrospinal fluid cytology and immunophenotyping: A case report

The cytologic findings of an extranodal NK/T‐cell lymphoma (NKTCL) presenting as a large adrenal mass with leptomeningeal involvement diagnosed by CT‐guided fine‐needle aspiration and cerebrospinal fluid (CSF) cytology are described. The 65‐year‐old Caucasian patient presented with progressive headache and multiple cranial nerve neuropathies. Magnetic resonance imaging showed leptomeningeal enhancement surrounding the conus medullaris and cauda equine, and a subsequent PET/CT demonstrated a large right adrenal gland mass. Fine‐needle aspiration of the adrenal mass showed occasional large pleomorphic cells with prominent nucleoli, moderate amounts of cytoplasm, and rare large cells with sparse cytoplasmic granules admixed with numerous small lymphocytes. Initial flow cytometry from this sample showed no clonal B‐cell population. Immunoperoxidase stains performed on the cell block/core specimen showed that the large atypical cells were positive for CD2, CD30, CD43 and CD56, TIA‐1, granzyme, and perforin, but for none of the other T‐cell markers used (CD3, CD4, CD5, CD8, CD45RO), which stained the abundant background lymphocytes. A CSF specimen showed similar neoplastic cells and flow cytometry showed an NK‐cell population with aberrant immunophenotype. The cytologic findings of the neoplastic cells and the extensive panel of immunoperoxidase stains allowed the diagnosis of NKTCL, which was confirmed by the subsequent flow‐cytometric immunophenotyping performed on the CSF. This is, to the best of our knowledge, the first case of NKTCL diagnosed by FNA of the adrenal gland and by CSF cytology. Diagn. Cytopathol. 2009. © 2009 Wiley‐Liss, Inc.     

Acute myeloid leukemia with myelodysplasia-related changes with erythroid differentiation involving pleural fluid: a case report and brief cytopathologic review

The vast majority of malignant pleural effusions are caused by metastatic adenocarcinoma, most frequently from breast or lung primaries. However, a minority of cases show evidence of involvement by a hematopoietic neoplasm such as lymphoma or leukemia. We report a rare case of a 54-year-old male with a prior diagnosis of acute myeloid leukemia with myelodysplastic-related changes (AML-MDS) with erythroid differentiation having new onset pleural effusions containing leukemic blasts. The pleural specimen was comprised of blast forms having large round nuclei with finely dispersed chromatin and prominent nucleoli, with scattered binucleate forms. The blasts expressed CD45 and CD34 and were negative for epithelial and mesothelial markers. Previous bone marrow biopsies had shown that the blasts exhibited strong staining for hemoglobin and lacked expression of Factor VIII and myeloperoxidase, consistent with erythroid differentiation. Although rare, this case indicates the need for consideration of unusual disease states presenting within a pleural fluid and highlights the differential diagnosis and immunohistochemical profile of AMLs with erythroid differentiation.     

Myelodysplastisches Syndrom (MDS)

Myelodysplastic syndromes (MDS) are a heterogenous group of clonal stem cell disorders which generally occur in older adults but may also affect children. Primary MDS should be distinguished from secondary MDS associated with antineoplastic or immunosuppressive therapy (t-MDS), exposure to toxic compounds, or genetic disorders. The establishment of a neoplastic clone is reflected by dysplastic features and impaired function which may affect all three hematopoietic cell lineages. The ineffective hematopoiesis which causes bone marrow failure is accompanied by peripheral blood cytopenia and is considered to result from increased apoptosis, at least in the less advanced MDS stages. The elucidation of the molecular pathogenesis of MDS has provided evidence that chromosomal abnormalities are present in about 50% of patients with primary MDS. They include numerical aberrations such as monosomy 5 or 7, trisomy 8, loss of the Y-chromosome and structural abnormalities such as deletion of the long arm of chromosome 5 (5q-syndrome), 7, or 8. Based on the percentage of blasts (<5%, 5-20%, 20-30%) and the presence of >15% ringed sideroblasts for marrows with <5% blasts, the French-American-British (FAB) classifies MDS into 4 morphologic categories: refractory anemia (RA), refractory anemia with excess of blasts (RAEB), refractory anemia with excess of blasts in transformation (RAEB-t), and refractory anemia with ringed sideroblasts. The fifth morphologic type is chronic myelomonocytic leukemia characterized by peripheral blood monocytosis (>1x10(9)/l). However, a modification of this classification will be proposed by the World Health Organization, with the intention of lowering the threshold for the diagnosis of AML from 30% to 20% blast cells. In patients presenting with cytopenias suggesting impaired hematopoiesis, the initial diagnosis depends mainly on the cytological evaluation of bone marrow and blood smears and the histological findings of trephine bone marrow biopsy. In a retrospective analysis we evaluated the occurrence of the distinct FAB-categories as percentage of the total number of MDS cases diagnosed at the Institute of Pathology of the University of Freiburg. A total of 63% fullfilled the criteria of RA/RARS, 17% of RAEB, 14% of RAEB-t, and 6% of CMML. A fibrotic variant of MDS was observed in 7.67% of all cases, ranging from 2.34% in RA up to 15. 42-15.84% in the categories which did not show significant differences with regard to myelofibrosis. The histologic evaluation of a trephine bone marrow biopsy is of critical importance for the evaluation of fibrotic or hypocellular MDS since these patterns are not reflected by the cytological examination. The combined cytological and histological diagnosis of bone marrow and peripheral blood is a reliable tool for the initial diagnosis of MDS. In addition, cytogenetic and molecular analysis should be performed. Presently, the risk of leukemic transformation is evaluated using the International Prognostic Scoring System for MDS, which is the sum of the scores of bone marrow blasts, karyotypes and cytopenia. In the context of clinical trials therapeutic modalities should be considerd according to the age and the general performance state and the prognostic scores of individual patients.     

Polymerase chain reaction on cerebrospinal fluid cells in suspected leptomeningeal involvement in childhood acute lymphoblastic leukemia: comparison to cytomorphological analysis.

The leptomeningeal involvement of central nervous system is defined in the most centers by the presence of blast cells in the CSF or the presence of cranial-nerve palsies. Sometimes, cytology does not allow clear distinction between lymphoblasts and normal cells, and auxiliary methods to the precise identification of leukemic cells in cerebrospinal fluid is necessary. We analyzed CSF from 11 consecutive patients, in whom a differential diagnosis of leptomeningeal involvement was made, including 4 patients at diagnosis and 7 patients during the treatment by cytomorphological analysis and PCR and automatic sequencing. Six patients were considered with leptomeningeal involvement by conventional analysis: unequivocal cytomorphological involvement was considered in 5 patients, and in one it was assumed to be due to cranial-nerve palsy, with no blast cells detected in cerebrospinal fluid. In 2 it was considered suspicious and in 3 negative. PCR and sequencing analysis showed involvement in 6 patients; 5 of the 6 patients were considered to have leptomeningeal involvement based on clinical and cytomorphological criteria, and, in one of the patients, it was suspicious. Our data suggest that the use of PCR and sequencing can be useful in confirming CNS leukemia and eliminating other conditions when used together with the cytomorphological analysis.     

Blastic Transformation of Essential Thrombocythemia

A case of blastic transformation of essential thrombocythemia (ET) is reported. A 69 year old male was first admitted to hospital because of fever in February, 1982. He was diagnosed as having ET because of marked thrombocytosis (205.5 ± 10¹⁰/1), absence of erythrocytosis, absence of splenomegaly, normal karyotype and no increment of blasts in the bone marrow, and normal levels of neutrophil alkaline phosphatase, vitamin B₁₂ and folate. He was treated with busulfan, and subsequently his platelet count was well controlled for about five years. At the second admission, blasts were present in the peripheral blood, and later accounted for 49% of the total leukocyte count. Histological examination of a bone biopsy specimen showed homogeneous proliferation of blastic cells and slight reticulin fibrosis. At autopsy, the degree of bone marrow fibrosis had increased. This was considered to be a very rare case of ET with blastic transformation in the terminal phase. Acta Pathol Jpn 39: 670-676, 1989.     

流式细胞术CD34+细胞计数在骨髓增生异常综合征分型诊断中的作用

为探讨流式细胞术(FCM)CD34+细胞计数在骨髓增生异常综合征(MDS)分型诊断中的应用价值.采用多参数FCM设门技术检测MDS患者骨髓CD34+细胞计数,与形态学分型诊断比较.结果显示:对照组和MDS组形态学原始细胞计数分别为0.43±0.64%和2.50±3.68%,FCM CD34+细胞计数分别为0.45±0....     

Long-lived plasma cells are generated in mucosal immune responses and contribute to the bone marrow plasma cell pool in mice

During systemic immune responses, plasma blasts are generated in secondary lymphoid organs and migrate to the bone marrow, where they can become long-lived, being responsible for the maintenance of long-term antibody titers. Plasma blasts generated in mucosal immune responses of the small intestine home to the lamina propria (LP), producing mainly immunoglobulin A. The migration of these antibody-secreting cells is well characterized during acute immune responses. Less is known about their lifetime and contribution to the long-lived bone marrow compartment. Here we investigate the lifetime of plasma cells (PCs) and the relationship between the PC compartments of the gut and bone marrow after oral immunization. Our findings indicate that PCs in the LP can survive for extended time periods. PCs specific for orally administered antigens can be detected in the bone marrow for at least 9 months after immunization, indicating that the mucosal PC compartment can contribute to the long-lived PC pool in this organ, independent of the participation of splenic B cells. Our findings suggest that the compartmentalization between mucosal and systemic PC pools is less strict than previously thought. This may have implications for the development of vaccines as well as for autoantibody-mediated diseases.     

Increased blasts mimicking acute leukemia in a patient with polysubstance abuse

Toxic insult to the bone marrow may result in partial or complete suppression, with or without reactive changes, and probable eventual regeneration of hematopoietic elements. During the regenerative process, increased blasts may be observed. Distinguishing these changes from an acute leukemic process can be difficult. In particular, the diagnosis of hypocellular bone marrow with increased blasts, also known as hypocellular or hypoplastic acute leukemia, presents a diagnostic dilemma for pathologists. We report a case of hypocellular marrow with increased blasts in a 50-year-old man with an extensive history of alcohol and drug abuse in whom chemotherapy was deferred. Recovery of peripheral blood cell counts and reticulocytosis occurred with withdrawal of the offending agents, and he remains alive and well 1 year later.     

The role of Janus Kinase 2 V617F mutation in extramedullary hematopoiesis of the spleen in neoplastic myeloid disorders.

Extramedullary hematopoiesis (EMH) in the spleen is a characteristic feature of the chronic myeloproliferative disorders (CMPDs) and various other neoplastic or reactive myeloid conditions. However, the origin of these hematopoietic precursor cells and the molecular mechanisms underlying their development in the spleen is uncertain. The V617F mutation in the Janus Kinase 2 gene (JAK2(V617F)) was recently shown to be frequently and preferentially present in the peripheral blood and bone marrow cells of CMPD patients, and the resulting dysregulation of its downstream targets is important to CMPD pathogenesis. To determine the occurrence and potential role of JAK2(V617F) in splenic EMH cells, we studied splenectomy specimens from 47 patients with significant EMH. JAK2(V617F) was detected by real-time PCR melting curve analysis in 22 specimens, including 11/17 chronic idiopathic myelofibrosis, 7/7 polycythemia vera, 1/1 essential thrombocythemia, 1/3 CMPD unclassifiable, 1/5 chronic myelomonocytic leukemia, 0/5 chronic myelogenous leukemia, 1/3 myelodysplastic syndrome and 0/6 acute myeloblastic leukemia cases, whereas only the JAK2 wild-type allele was detected in the other 25. Nineteen of 20 cases with adequate bone marrow samples available for molecular examination demonstrated concordant JAK2 genotypes. Laser-capture microdissection was then used to enrich the EMH and non-EMH splenic cell fractions, confirming that the mutant alleles specifically originated from the EMH cells. Furthermore, megakaryocytes in the JAK2(V617F)-positive splenectomy specimens expressed higher levels of Bcl-xL, an antiapoptotic protein and downstream target of the JAK2/STAT5 pathway. Thus, JAK2(V617F) is frequently present in splenic EMH cells associated with CMPD, but it is rarely identified in splenic EMH cells associated with other myeloid disorders. Our results indicate that the precursor cells leading to extramedullary hematopoietic expansion in CMPD most likely originate from the transformed bone marrow clone. Also, dysregulation of downstream pathways such as Bcl-xL may be important to CMPD disease pathogenesis in the spleen.     

Granulocytic sarcoma of breast: an aleukemic presentation

Granulocytic sarcoma is a rare extramedullary tumor composed of immature myeloid cells. It is usually associated with leukemia or other myeloproliferative disorders but can also occur without overt hematologic diseases. The breast is an uncommon site of presentation and requires a high index of suspicion for diagnosis. We report such a case in a 45-year-old female, who presented with nontender left breast lump of 6 months' duration. A peripheral smear and bone marrow examination at that time was normal. A lumpectomy was done. An H and E diagnosis of lobular carcinoma vs. non-Hodgkin's lymphoma was entertained. Immunostains, however, revealed myeloperoxidase, naphthol AS-D chloroacetate esterase and CD43 positivity, indicating a diagnosis of granulocytic sarcoma. It appears that early initiation of systemic AML-type chemotherapy is beneficial and may delay or avert the development of AML in bone marrow and blood. Eight months later, the patient presented with an orbital mass; bone marrow and peripheral smear involvement by AML.     

Cytomembranous Inclusions in Myelodysplastic Syndrome

A 56-year-old African-American man presented with fever of unknown origin and peripheral blood and bone marrow findings of myelodysplastic syndrome (MDS): refractory anemia with an excess of blasts in transformation that subsequently progressed to acute myeloblastic leukemia (AMD. Ultrastructural study of two bone marrow specimens having the findings of MDS revealed frequent, large tubuloreticular structures (TRS) in lymphocytes, plasma cells, macrophages, and endothelial cells. Several cylindrical confronting cisternae (CCC) were present in macrophages and an endothelial cell. Two partially developed CCC were present in a plasma cell. TRS and CCC were not observed in eight subsequent bone marrow specimens obtained during the 9-month course of the AML. This is the first reported occurrence of TRS and CCC in MDS. These inclusions are probably related to an unidentified viral infection or possibly to cytokines released by the dysplastic hematopoietic cells.     

Dermal monocytic sarcoma/monoblastic tumour: report of two cases of acute monocytic leukemia with initial dermal manifestations only

The clinical and pathological findings in 2 patients with acute monocytic leukemia (AMOL) presenting initially as multiple monoblastic tumours of the skin (monocytic sarcoma) were reviewed. The skin biopsies were originally interpreted as malignant lymphoma and the diagnosis of AMOL was established when overt bone marrow and/or peripheral blood involvement was detected. The time interval from initial skin biopsy to either blood or bone marrow involvement by AMOL was 2 and 18 mth. After diagnosis of extracutaneous dissemination, survival was less than 1 mth. Cytochemistry, immunohistochemistry and electron microscopy can aid in the diagnosis of a monocytic sarcoma. Generally, the most practical way to confirm the diagnosis, in everyday practice, on fixed paraffin-embedded tissues is the demonstration of alpha-1-antitrypsin (A1AT) and/or lysozyme by the immunoperoxidase technique.