Clinical and prognostic significance of 3q26.2 and other chromosome 3 abnormalities in CML in the era of tyrosine kinase inhibitors.

Chromosome 3q26.2 abnormalities in acute myeloid leukemia, including inv(3)/t(3;3) and t(3;21), have been studied and are associated with a poor prognosis. Their prevalence, response to tyrosine kinase inhibitor (TKI) treatment, and prognostic significance in chronic myelogenous leukemia (CML) are largely unknown. In this study, we explored these aspects using a cohort of 2013 patients with CML diagnosed in the era of TKI therapy. Chromosome 3 abnormalities were observed in 116 (5.8%) of 2013 cases. These cases were divided into 5 distinct groups: A, inv(3)(q21q26.2)/t(3;3)(q21;q26.2), 26%; B, t(3;21)(q26.2;q22), 17%; C, other 3q26.2 rearrangements, 7%; D, rearrangements involving chromosome 3 other than 3q26.2 locus, 32%; and E, gain or loss of partial or whole chromosome 3, 18%. In all, 3q26.2 rearrangements were the most common chromosome 3 abnormalities (50%, groups A-C). 3q26.2 rearrangements emerged at different leukemic phases. For cases with 3q26.2 rearrangements that initially emerged in chronic or accelerated phase, they had a high rate of transformation to blast phase. Patients with 3q26.2 abnormalities showed a marginal response to TKI treatment, and no patients achieved a long-term sustainable response at a cytogenetic or molecular level. Compared with other chromosomal abnormalities in CML, patients with 3q26.2 rearrangements had poorer overall survival. The presence or absence of other concurrent chromosomal abnormalities did not affect survival in these patients, reflecting the predominant role of 3q26.2 rearrangements in determining prognosis. Interestingly, although heterogeneous, chromosome 3 abnormalities involving non-3q26.2 loci (groups D, E) also conferred a worse prognosis compared with changes involving other chromosomes in this cohort.

Ferritin H is a novel marker of early erythroid precursors and macrophages.

AIMS: Macrophages play a critical role in iron homeostasis by recycling iron from red cells and storing it in ferritin, an iron storage protein. The recycled iron is delivered to erythroid precursors for erythropoiesis. In this study, we aimed to determine whether ferritin is highly expressed in macrophages and erythroid precursors, and whether it can be used as a marker for these two cell types. METHODS AND RESULTS: A ferritin monoclonal antibody was developed, and immunohistochemistry was performed. In normal bone marrows, ferritin antibody stained early erythroid precursors and macrophages. In contrast, myeloid cells, lymphoid cells and megakaryocytes lacked ferritin expression. In leukaemic bone marrows, ferritin was selectively expressed in erythroid blasts (M6), whereas all other blasts were negative. In lymph nodes, ferritin was highly and specifically expressed in macrophages, whereas lymphocytes completely lacked ferritin expression. In non-haematopoietic tissues, ferritin antibody highlighted alveolar macrophages in the lung, as well as sinus macrophages in the liver and spleen. CONCLUSIONS: We conclude that ferritin is a novel and reliable marker for macrophages and early erythroid precursors, and may be of clinical utility in the diagnosis of diseases associated with these two cell types.

Composite B-cell and T-cell lineage post-transplant lymphoproliferative disorder of the lung with unusual cutaneous manifestations of mycosis fungoides.

We present the case of a 17-year-old male kidney transplant recipient who presented initially with dermatologic symptoms and was found to have histologic changes in the skin that were consistent with mycosis fungoides. Shortly after this diagnosis was made, imaging studies demonstrated multifocal interstitial and airspace consolidation in both lungs. Physical examination revealed no lymphadenopathy or hepatosplenomegaly, but an open lung biopsy revealed an Epstein-Barr virus (EBV)-negative monomorphic T-cell posttransplant lymphoproliferative disorder (PTLD) with a concomitant EBV-positive B-cell PTLD involving the same lesion of the lung. Polymerase chain reaction analysis demonstrated clonal T-cell receptor gene rearrangements in both the skin and the lung biopsies. Interestingly, 1 clone was shared between the skin and lung while a second clone was present only in the lung. To our knowledge, this is the first reported case of a PTLD presenting in the skin in which there was a subsequent discovery of composite, bilineal B- and T-cell PTLD of the lung.

Cardiac Involvement by Human Herpesvirus 8-Positive Diffuse Large B-Cell Lymphoma: An Unusual Presentation in a Patient with Human Immunodeficiency Virus.

Human immunodeficiency virus (HIV) infection predisposes patients to the development of lymphomas, both due to immune suppression and coinfection with viruses with oncogenic potential. Coinfection with human herpesvirus 8 (HHV8) in particular has been associated with the development of aggressive lymphomas, including primary effusion lymphoma and diffuse large B-cell lymphoma (DLBCL). Herein, we report an unusual case of HHV8-positive DLBCL with extensive cardiac involvement which was diagnosed at autopsy in a patient with long-standing untreated HIV infection.

PML-RARA Fusion Transcripts Detectable 8 Months prior to Promyelocytic Blast Crisis in Chronic Myeloid Leukemia.

Promyelocytic blast crisis arising from chronic myeloid leukemia (CML) is rare. We present a 40-year-old male who developed promyelocytic blast crisis 17 months after CML diagnosis, confirmed by the presence of the t(15;17) and t(9;22) translocations in the leukemic cells. Preserved nucleic acids from routine BCR-ABL1 testing provided a unique opportunity to evaluate clonal progression over time. Retrospective analysis demonstrated PML-RARA fusion transcripts were first detectable 8 months prior to blast crisis presentation. A review of 21 cases of promyelocytic blasts crisis published in the literature reveals a male predominance with earlier age at onset as compared to females. Interestingly, TKI therapy during chronic phase did not impact the time interval between diagnosis and promyelocytic blast crisis. Treatment with standard acute promyelocytic leukemia regimens provides more favorable outcomes with complete molecular remission. Although rare, it is important to consider a promyelocytic blast crisis when evaluating for transformation of CML due to its effective treatment with specific therapies.

Diagnostic pitfalls associated with fine-needle aspiration biopsy in a patient with the myxoid variant of monophasic fibrous synovial sarcoma.

Synovial sarcoma (SS) is one of the most common soft tissue tumors that typically presents in the extremities of young adults, but may occur at any site and affect children during the first decade. Herein we discuss a 12-yr-old male who complained of left foot pain and plantar mass. A fine-needle aspiration biopsy of an 8 cm subcutaneous mass was performed revealing a myxoid spindle cell neoplasm. The cytologic differential diagnosis included a myxoid neurofibroma, neurothekeoma, and a myxoid sarcoma. Subsequent excision of the mass revealed a monophasic fibrous SS with myxoid features. Examination of the tissue by fluorescence in situ hybridization confirmed the presence of characteristic SS SYT gene rearrangement at chromosome 18q11.2. This case underscores that the cytologic distinction of mxyoid spindle cell tumors may be challenging. We report the cytologic features of a myxoid monophasic fibrous SS, and discuss its distinction from other benign and malignant myxoid soft tissue neoplasms.

Hodgkin lymphoma: flow me?

Combining fine needle aspirate cytology with flow cytometry immunophenotyping for the rapid diagnosis of lymphoproliferative lesions is commonplace practice in many institutions. Yet, a definitive diagnosis of Hodgkin lymphoma in many cases remains elusive, requiring subsequent tissue biopsy confirmation. In this issue of CytoJournal, Hernandez et al explore the potential role of using the increased CD4/CD8 T-cell ratio in lymph node fine needle aspiration specimens as a specific feature in diagnosing Hodgkin lymphoma. CD4/CD8 T-cell ratio comparisons are made with cytomorphologic diagnoses of reactive, atypical, non-Hodgkin lymphoma, and Hodgkin lymphoma cases.

Loss of heterozygosity on chromosome 1 and 9 and hormone receptor analysis of metastatic malignant melanoma presenting in breast.

Malignant melanoma (MM), the most common metastatic solid tumor to involve the breast, may present as a diagnostic problem, frequently requiring the use of ancillary studies for accurate diagnosis. The implication of hormonal interplay is strong since metastatic MM to the breast is seen nearly always in women. However, the role of hormonal status as a predisposing factor in the development of this entity is largely unresolved. A number of chromosomal loci, including 1p36 and 9p21-22, appear to harbor critical genes important to melanoma tumorigenesis, and additionally chromosome 9q22.3-31. We wanted to know if metastatic MM in breast showed chromosome 1p and 9p genetic alterations (loss of heterozygosity) similar to those that occur in primary cutaneous MM, and whether additional 9q LOH changes are present. Hormonal receptor status of the metastatic MM was also determined. We identified 20 patients with known MM metastatic to the breast, which we analyzed with the following genetic markers: D9S12 (9q22.3), D9S171 (9p21), IFNA (9p22), and D1S450 (1p). Visually directed microdissection was performed on archival histologic slides containing both tumor and adjacent normal breast epithelium, followed by single-step DNA extraction and polymerase chain reaction (PCR) amplification for evaluation of loss of heterozygosity (LOH) for the above-listed markers. Immunohistochemical (IHC) stains for estrogen receptor (ER) and progesterone receptor (PR) was performed on 10 of the cases. Twelve of the 20 cases contained DNA suitable for PCR amplification following direct visualization microdissection. Four of 8 (50%) informative cases showed LOH at 9p21 with D9S171. Ten cases were heterozygous for IFNA, with 2 cases (20%) showing LOH at this locus. These particular cases also showed LOH at 9p21. One of 9 (11%) informative cases showed LOH for D1S450 (1p36). Five cases were heterozygous for D9S12, and 2 (40%) showed LOH in the tumor at 9q22.3. IHC stains for ER and PR were negative in the 10 tumors studied. Metastatic MM presenting as a breast mass is an interesting entity often requiring IHC studies for diagnosis, particularly when the histologic features simulate breast carcinoma or when no primary tumor is known. These tumors are ER and PR negative. Metastatic MM involving the breast shows similar genetic allelic losses on chromosome 9p21-22 (50%) and 1p36 (11%), as previously described in primary cutaneous MM. Additional LOH was observed at the 9q22.3-31 locus (40%). We suggest this locus to be investigated for harboring potential genes important in the tumorigenesis of cutaneous MM.

Donor-derived myeloid sarcoma in two kidney transplant recipients from a single donor.

We report the rare occurrence of donor-derived myeloid sarcoma in two kidney transplant patients who received organs from a single deceased donor. There was no evidence of preexisting hematologic malignancy in the donor at the time of organ recovery. Both recipients developed leukemic involvement that appeared to be limited to the transplanted organ. Fluorescence in situ hybridization (FISH) and molecular genotyping analyses confirmed that the malignant cells were of donor origin in each patient. Allograft nephrectomy and immediate withdrawal of immunosuppression were performed in both cases; systemic chemotherapy was subsequently administered to one patient. Both recipients were in remission at least one year following the diagnosis of donor-derived myeloid sarcoma. These cases suggest that restoration of the immune system after withdrawal of immunosuppressive therapy and allograft nephrectomy may be sufficient to control HLA-mismatched donor-derived myeloid sarcoma without systemic involvement.

Intracranial pseudolymphoma presenting with grand mal seizures.

Primary central nervous system lymphoproliferative disorders comprise a heterogenous group of intracranial disease, predominantly of the high-grade non-Hodgkin's lymphoma type. We report a 56-year-old woman who developed new-onset grand mal seizures and was found to have two small uniformly enhancing dural-based lesions, which were radiologically concerning for meningiomas. Biopsy demonstrated findings consistent with benign, reactive lymphoid tissue. The patient's seizures resolved post-operatively. To our knowledge, this is the first reported patient with intracranial pseudolymphoma presenting as grand mal seizures. This case highlights this rare differential consideration in a patient with symptomatic dural-based lesion.

Concomitant occurrence of sinus histiocytosis with massive lymphadenopathy and nodal marginal zone lymphoma.

Sinus histiocytosis with massive lymphadenopathy (SHML), also known as Rosai-Dorfman disease, is a rare self-limiting disorder of histiocytes with unknown etiology. Sinus histiocytosis with massive lymphadenopathy is most common in children and young adults and is characterized by painless lymphadenopathy. Histologically there is a proliferation of sinus histiocytes with lymphophagocytosis or emperipolesis. On rare occasions, SHML has been associated with lymphoma, usually involving different anatomic sites and developing at different times. We report a case of concomitant SHML and nodal marginal zone lymphoma involving the same lymph node without involvement of other nodal or extranodal sites. The presence of concomitant SHML within the lymph node involved by nodal marginal zone lymphoma may represent the responsiveness of SHML histiocytes to B-cell-derived cytokines in lymphoproliferative disorders. To our knowledge, this is the first description of concomitant occurrence of SHML and nodal marginal zone lymphoma.

Possible role of engraftment syndrome and autologous graft-versus-host disease in myelodysplastic syndrome after autologous stem cell transplantations: retrospective analysis and review of the literature.

BACKGROUND: We report a retrospective study of 452 patients with lymphoma from 1991 to 2006, with 274 men and 178 women, median age of 50 years (range, 16-76 years). PATIENTS AND METHODS: There were 85 patients with Hodgkin lymphoma (HL) and 367 with non-Hodgkin lymphoma (NHL). Eleven patients received a second autologous transplantation for progressive lymphoma, and another 4 received a second allogeneic transplantation for myelodysplastic syndrome (MDS). Twenty-seven patients had skin biopsies, and 2 patients had gastrointestinal biopsies consistent with graft-versus-host disease (GVHD), and 11 patients developed severe engraftment syndrome (ES), as defined by noninfectious fever and skin rash with or without pulmonary infiltrates requiring systemic steroids. RESULTS: The median follow-up of the patients was 6.2 years, and median overall survival was 5.3 years. Twenty-four patients (5.3%) developed MDS with median time of onset of 4.2 years (range, 8 months to 7.5 years). An additional 5 patients developed clonal karyotypic abnormalities in the bone marrow without clinical MDS. Actuarial probabilities of developing MDS at 5 and 8 years after transplantation were 5% and 15%, respectively. CONCLUSION: The incidences of MDS are similar in HL and NHL. Multivariate analysis revealed older age, occurrence of ES/GVHD, and longer intervals between the initial diagnoses to transplantation as independent factors. It is conceivable that perturbation to the host immunity caused by either previous chemotherapy or conditioning regimens in the elderly might play a role in the development of MDS after autologous transplantation.

Kimura's disease: a diagnostic challenge.

Kimura's disease is a rare inflammatory disorder of unknown cause, primarily seen in young Asian males. The disease is characterized by a triad of painless subcutaneous masses in the head or neck region, blood and tissue eosinophilia, and markedly elevated serum immunoglobulin E levels. We describe an 11-year-old Asian boy with Kimura's disease who presented with a chronic left neck mass. The diagnosis was based on the characteristic histopathologic findings after surgical excision in conjunction with peripheral eosinophilia and elevated serum immunoglobulin E levels. Pediatricians in western countries should be aware of the clinical presentation of Kimura's disease.