A young man, presented with high-grade fever and disseminated asymptomatic skin lesions of 6-weeks duration. Cutaneous examination revealed multiple infiltrated monomorphic skin-colored papules and nodules upto 2×2 cm all over scalp, face, trunk and extremities. Light microscopy of nodules showed diffuse infiltration of dermis and subcutis by a tumor composed of medium to large cells with round to ovoid nuclei with fine chromatin, few with visible nucleoli and scanty to moderate amounts of eosinophilic cytoplasm. Tumor cells were positive for CD4, CD8, CD56 and negative for CD30, terminal deoxynucleotidyl transferase and Alk-1. Excised axillary lymph node showed similar morphologic and immunohistochemical findings. There was bone marrow involvement with infiltrate of large atypical/immature lymphoid cells. Diagnosis of blastic plasmacytoid dendritic cell neoplasm was made. This is a rare neoplasm. presenting commonly in the skin, with or without concurrent extracutaneous disease.
Blastic plasmacytoid dendritic cell neoplasm; cutaneous nodules; fever
Oncocytic carcinoma is an extremely rare neoplasm of the salivary gland, with only a few cases reported in literature till date. We report the occurrence of this rare lesion in lip in a 43-year-old female presenting with a progressively increasing swelling for which excision was done. Fine needle aspiration was done and the smears revealed tumor cells with well-defined cell borders, round to oval, central to eccentrically located moderately pleomorphic nuclei with fine chromatin, prominent nucleoli and abundant eosinophilic granular cytoplasm. Microscopic examination of the resected tumor showed solid sheets, nests, islands and cords of oncocytic cells diffusely infiltrating the surrounding tissues. After 5 months, the patient again presented with bilateral submandibular and right axillary lymphadenopathy revealing metastatic deposits from oncocytic carcinoma. We report this case of oncocytic carcinoma because of its unusual location, the minor salivary gland of lip being a rare site for the tumor.
Lip; minor salivary gland; oncocytic carcinoma
Children with neurofibromatosis type 1 (NF1) are predisposed to juvenile myelomonocytic leukemia (JMML), an aggressive myeloproliferative neoplasm (MPN) that is refractory to conventional chemotherapy. Conditional inactivation of the Nf1 tumor suppressor in hematopoietic cells of mice causes a progressive MPN that accurately models JMML and chronic myelomonocytic leukemia (CMML). We characterized the effects of Nf1 loss on immature hematopoietic populations and investigated treatment with the MEK inhibitor PD0325901 (hereafter called 901). Somatic Nf1 inactivation resulted in a marked expansion of immature and lineage-committed myelo-erythroid progenitors and ineffective erythropoiesis. Treatment with 901 induced a durable drop in leukocyte counts, enhanced erythropoietic function, and markedly reduced spleen sizes in mice with MPN. MEK inhibition also restored a normal pattern of erythroid differentiation and greatly reduced extramedullary hematopoiesis. Remarkably, genetic analysis revealed the persistence of Nf1-deficient hematopoietic cells, indicating that MEK inhibition modulates the proliferation and differentiation of Nf1 mutant cells in vivo rather than eliminating them. These data provide a rationale for performing clinical trials of MEK inhibitors in patients with JMML and CMML.
Myoepitheliomas are benign neoplasms of salivary glands derived from myoepithelial cells. These tumors can occur at any age but are most common in young adults. This tumor is usually located in the parotid gland and the minor salivary glands of the soft palate and represents less than 1% of all salivary gland tumors. The myoepithelioma is classified in the follow cells types: spindle, plasmacytoid, reticular, epitheliod, and clear, additionally, mixed histological forms are described. The plasmacytoid myoepithelioma from palate salivary glands is considered as a rare entity. A 45-year-old lady presented with an asymptomatic, well-circumscribed, solid mass located on the hard palate, which was gradually increasing in size. A clinical impression of Pleomorphic Adenoma was made which on histopathological examination revealed cords, clusters, and sheets of homogenous, large cells with plasmacytoid characteristics and a prominent eosinophilic cytoplasm. Ductal and acinar differentiation were absent thus ruling out the pleomorphic adenoma, whereas, features consistent with plasmacytoid myoepithelioma were evident.
Myoepithelioma; minor salivary gland tumor; plasmacytoid
Although plasma cells are terminally differentiated B cells, neoplastic plasma cells frequently express not only pre-B cell antigen, but also megakaryocytic, myelomonocytic, or erythroid markers. Since morphologic diagnosis of plasmacytoma is based on the recognition of neoplastic cells closely resembling normal plasma cells, unusual morphologic variants of neoplastic cells associated with these aberrant immunohistochemical features frequently cause diagnostic difficulty. The authors report a case of plasmacytoma with cleaved nuclei and myelomonocytic features occurring in the clavicle. The tumor was composed of immature plasma cells showing irregular, cleaved, and multilobated nuclei and abundant cytoplasm with prominent eosinophilic granules. A few tumor cells showing recognizable plasmacytic differentiation were admixed within the tumor. Immunohistochemically, the tumor cells expressed CD45RB, CD68, lysozyme, myeloperoxidase and kappa light chain with focal positivity for lambda chain. Ultrastructurally, the tumor cells contained numerous membrane bound electron dense lysosomal granules, some of them resembling Auer rods, as well as rough endoplasmic reticula arranged in lamellated stacks. Small biopsied nasal mucosal tissue in same patient revealed well differentiated plasmacytoma composed of tumor cells showing round, eccentric nuclei devoid of marked nuclear cleavage and cytoplasmic granularity. Immunohistochemically, these cells were kappa(+), lambda(-), myeloperoxidase(-), lysozyme(-) and CD68(-).
The monoclonal antibody 6C3 was used to test a wide variety of murine hematopoietic neoplasms for cell surface expression of a 160 kD glycoprotein (gp160(6C3)) previously shown to be expressed by neoplastic pre-B and some B lymphocytes transformed by Abelson murine leukemia virus (A-MuLV). This antigen was expressed on many pre-B and B cell lymphomas, but not on A-MuLV-transformed fibroblasts, T cell lymphomas, or myelomonocytic leukemias, gp160(6C3) was expressed by most early B-lineage spontaneous tumors, and early B tumors induced by replication-defective MuLV-containing oncogenes the products of which are associated with the cytoplasmic aspect of the plasma membrane, i.e., fes, abl, H-ras, bas, src, erbB, and Cas NS-1. By comparison, none of the early B lineage lymphomas induced by the "nuclear" oncogene avian v-myc MuLV, or arising in mice transgenic for a murine c-myc gene, or later B cell lineage stages bearing translocations of the c- myc locus expressed this antigen.
Myoepithelioma of the breast is very rare. Breast myoepithelioma can develop in women from their early 20s right up to their 80s, but it is most common in women over 50. We report a case of 20-year-old female, who presented with a well-defined breast lump of 3 × 3 cm in size. Fine needle aspiration was performed. The cytological findings revealed good cellularity comprising monomorphic loosely cohesive sheets of plasmacytoid, round to polygonal cells with round to ovoid eccentrically placed nuclei, finely dispersed chromatin, and moderate amount of cytoplasm. On the basis of cytological findings, a diagnosis of benign myoepithelioma (plasmacytoid type) was made which was confirmed on histopathologic examination. The breast is a very rare localization for this type of tumor. The benign character of the disease in conjunction with its slow progression could delay its detection and diagnosis. A detailed pathology examination is a prerequisite for avoidance of misleading diagnosis.
Breast; myoepithelioma; fine needle aspiration
Juvenile myelomonocytic leukemia (JMML) is characterized by myelomonocytic cell overproduction and commonly bears activating mutations in PTPN11. Murine hematopoietic progenitors expressing activating Shp2 undergo myelomonocytic differentiation, despite being subjected to conditions that normally support only mast cells. Evaluation of hematopoietic-specific transcription factor expression indicates reduced GATA2 and elevated c-Jun in mutant Shp2-expressing progenitors. We hypothesized that mutant Shp2-induced Ras hyperactivation promotes c-Jun phosphorylation and constitutive c-Jun expression, permitting, as a coactivator of PU.1, excessive monocytic differentiation and reduced GATA2. Hematopoietic progenitors expressing activating Shp2 demonstrate enhanced macrophage CFU (CFU-M) compared to that of wild-type Shp2-expressing cells. Treatment with the JNK inhibitor SP600125 or cotransduction with GATA2 normalizes activating Shp2-generated CFU-M. However, cotransduction of ΔGATA2 (lacking the C-terminal zinc finger, needed to bind PU.1) fails to normalize CFU-M. NIH 3T3 cells expressing Shp2E76K produce higher levels of luciferase expression directed by the macrophage colony-stimulating factor receptor (MCSFR) promoter, which utilizes c-Jun as a coactivator of PU.1. Coimmunoprecipitation demonstrates increased c-Jun-PU.1 complexes in mutant Shp2-expressing hematopoietic progenitors, while chromatin immunoprecipitation demonstrates increased c-Jun binding to the c-Jun promoter and an increased c-Jun-PU.1 complex at the Mcsfr promoter. Furthermore, JMML progenitors express higher levels of c-JUN than healthy controls, substantiating the disease relevance of these mechanistic findings.
Notch signaling is a central regulator of differentiation in a variety of organisms and tissue types1. Its activity is controlled by the multi-subunit γ–secretase complex (γSE) complex2. Although Notch signaling can play both oncogenic and tumor suppressor roles in solid tumors, in the hematopoietic system, it is exclusively oncogenic, notably in T cell acute lymphoblastic leukemia (T-ALL), a disease characterized by Notch1 activating mutations3. Here we identify novel somatic inactivating Notch pathway mutations in a fraction of chronic myelomonocytic leukemia (CMML) patients. Inactivation of Notch signaling in mouse hematopoietic stem cells (HSC) resulted in an aberrant accumulation of granulocyte/monocyte progenitors (GMP), extramedullary hematopoieisis and the induction of CMML-like disease. Transcriptome analysis revealed that Notch signaling regulates an extensive myelomonocytic-specific gene signature, through the direct suppression of gene transcription by the Notch target Hes1. Our studies identify a novel role for Notch signaling during early hematopoietic stem cell differentiation and suggest that the Notch pathway can play both tumor-promoting and suppressive roles within the same tissue.
The T cell immunoglobulin mucin (TIM) proteins are a family of cell surface phosphatidyserine receptors that are important for the recognition and phagocytosis of apoptotic cells. Because TIM-4 is expressed by macrophages and dendritic cells in human tissue, we examined its expression in a range of histiocytic and dendritic cell neoplasms and found moderate to strong immunohistochemical staining in cases of juvenile xanthogranuloma and histiocytic sarcoma, and lower level staining in interdigitating dendritic cell sarcoma, Langerhans cell histiocytosis, acute monocytic leukemia (leukemia cutis), and blastic plasmacytoid dendritic cell neoplasm (hematodermic tumor). TIM-3 was first described on activated TH1 cells but was recently shown to also be a phosphatidylserine receptor and mediate phagocytosis. We found TIM-3 was expressed by peritoneal macrophages, monocytes and splenic dendritic cells. We found that it, like TIM-4, is expressed in a range of histiocytic and dendritic cell neoplasms, typically with strong immunohistochemical staining. Cases of diffuse large B cell lymphoma, anaplastic large cell lymphoma, metastatic malignant melanoma, and metastatic poorly differentiated carcinoma generally exhibited negative to minimal heterogenous staining for TIM-4 and TIM-3. We conclude that histiocytic and dendritic cell neoplasms consistently express TIM-3 and TIM-4 and that these molecules are new markers of neoplasms derived from histiocytic and dendritic cells.
Interdigitating dendritic cell sarcoma; Follicular dendritic cell sarcoma; Juvenile xanthogranuloma; Blastic plasmacytoid dendritic cell neoplasm; Leukemia cutis; Langerhans cell histiocytosis; T cell immunoglobulin mucin protein
Myeloid malignant diseases comprise chronic (including myelodysplastic syndromes, myeloproliferative neoplasms and chronic myelomonocytic leukemia) and acute (acute myeloid leukemia) stages. They are clonal diseases arising in hematopoietic stem or progenitor cells. Mutations responsible for these diseases occur in several genes whose encoded proteins belong principally to five classes: signaling pathways proteins (e.g. CBL, FLT3, JAK2, RAS), transcription factors (e.g. CEBPA, ETV6, RUNX1), epigenetic regulators (e.g. ASXL1, DNMT3A, EZH2, IDH1, IDH2, SUZ12, TET2, UTX), tumor suppressors (e.g. TP53), and components of the spliceosome (e.g. SF3B1, SRSF2). Large-scale sequencing efforts will soon lead to the establishment of a comprehensive repertoire of these mutations, allowing for a better definition and classification of myeloid malignancies, the identification of new prognostic markers and therapeutic targets, and the development of novel therapies. Given the importance of epigenetic deregulation in myeloid diseases, the use of drugs targeting epigenetic regulators appears as a most promising therapeutic approach.
The rare variant of renal epithelioid/pleomorphic angiomyolipoma has been reported in approximately 120 cases. One of the most important characteristics to differentiate these tumors from other renal cell neoplasms is their typical reactivity to premelanosome antigens. If such a tumor does not stain for HMB-45 or Melan-A, a specific diagnosis of epithelioid pleomorphic angiomyolipoma cannot be made with certainty.
We present here what is, to the best of our knowledge, the first case of epithelioid/pleomorphic angiomyolipoma of the kidney in a 50-year-old Caucasian man with no history of tuberous sclerosis, and with a tumor marker profile negative for several premelanosome antigens. The tumor was composed of sheets of pleomorphic, round to polygonal epithelioid cells with prominent eosinophilic cytoplasm, large nuclei, many multinucleated, and very prominent nucleoli. There were prominent vessels and rare interspersed smooth muscle fibers, but adipocytes were not identified. A tumor marker profile showed tumor cell reactivity for CD68, calponin and focally for CD10. Intervening smooth muscle was reactive with smooth muscle actin. The tumor lacked reactivity for melanin-associated antigens HMB-45 and Melan-A, and for CD31, pan-cytokeratin (AE1/3) and desmin. Electron microscopic examination of tumor cells confirmed the presence of premelanosome-like granules.
Based on the characteristic microscopic appearance of this tumor, and its overall tumor marker profile, we concluded this was a renal epithelioid/pleomorphic angiomyolipoma with a negative premelanosome antigen phenotype.
This is the first case report of Histiocytic Sarcoma (HS) with predominant spindle cell component occurring in the head and neck region of a 41-year-old man. The tumor was composed of sheets of large round to oval cells with pleomorphic vesicular nuclei, prominent nucleoli and abundant eosinophilic cytoplasm. Multinucleated forms, numerous mitoses, and tumor necrosis were also noted. Sheets, fascicles, and whorls of spindle cells with spindled to ovoid vesicular nuclei, small to medium-sized distinct nucleoli, and eosinophilic cytoplasm were frequently observed. Immunohistochemical staining in the tumor cells was positive for CD163, CD68, lysozyme, CD45, and NSE. Focal expression of CD4 and S-100 was also noted. Electron microscopy demonstrated an abundance of lysosomes in the cytoplasm of tumor cells. Chromosome study revealed a 57–80 hyperdiploid /46, XY  karyotype, including 3 to 4 copies of various chromosomes. The immunohistochemical and ultrastructural findings confirmed the diagnosis of HS.
A series of monoclonal antibodies have been characterized that define four surface antigens (MY3, MY4, MY7, and MY8) of human myeloid cells. They were derived from a fusion of the NS-1 plasmacytoma cell line with splenocytes from a mouse immunized with human acute myelomonocytic leukemia cells. MY3 and MY4 are expressed by normal monocytes and by greater than 90% of patients with acute monocytic leukemia or acute myelomonocytic leukemia, but are detected much less often on other types of myeloid leukemia. MY7 is expressed by granulocytes, monocytes, and 5% of normal bone marrow cells. 79% of all acute myeloblastic leukemia (AML) patients tested (72 patients) express MY7 without preferential expression by any AML subtype. MY8 is expressed by normal monocytes, granulocytes, all peroxidase-positive bone marrow cells, and 50% of AML patients. MY3, MY4, and MY8 define myeloid differentiation antigens in that they are not detected on myeloid precursor cells and appear at discrete stages of differentiation. These antigens are not expressed by lymphocytes, erythrocytes, platelets, or lymphoid malignancies. The monoclonal antisera defining these antigens have been used to study differentiation of normal myeloid cells and malignant cell lines.
Dendritic cell (DC) defects are an important component of immunosuppression in cancer. Here, we assessed whether cancer could affect circulating DC populations and its correlation with tumor progression. The blood DC compartment was evaluated in 136 patients with breast cancer, prostate cancer, and malignant glioma. Phenotypic, quantitative, and functional analyses were performed at various stages of disease. Patients had significantly fewer circulating myeloid (CD11c+) and plasmacytoid (CD123+) DC, and a concurrent accumulation of CD11c-CD123- immature cells that expressed high levels of HLA-DR+ immature cells (DR+IC). Although DR+IC exhibited a limited expression of markers ascribed to mature hematopoietic lineages, expression of HLA-DR, CD40, and CD86 suggested a role as antigen-presenting cells. Nevertheless, DR+IC had reduced capacity to capture antigens and elicited poor proliferation and interferon-γ secretion by T-lymphocytes. Importantly, increased numbers of DR+IC correlated with disease status. Patients with metastatic breast cancer showed a larger number of DR+IC in the circulation than patients with local/nodal disease. Similarly, in patients with fully resected glioma, the proportion of DR+IC in the blood increased when evaluation indicated tumor recurrence. Reduction of blood DC correlating with accumulation of a population of immature cells with poor immunologic function may be associated with increased immunodeficiency observed in cancer.
Solid tumors; dendritic cell subsets; immune dysfunction; immature antigen-presenting cell; breast cancer
Soft tissue myoepithelioma is a rare neoplasm composed of myoepithelial cells. Here, we describe the cytologic features of soft tissue myoepithelioma arising on the right forearm in an 18-year-old man. The excised tumor (3.0×1.8×1.5 cm) was well-demarcated, yellow-gray, soft, and myxoid. The cytologic smears showed round to spindle, epithelioid, and plasmacytoid cells in the myxoid background. The nuclei were uniform, round to ovoid, with finely distributed chromatin and eosinophilic or pale cytoplasm. The tumor cells demonstrated immunoreactivity for cytokeratin (AE1/AE3), epithelial membrane antigen, S100 protein, and glial fibrillary acidic protein. Electron microscopy showed intermediate filaments, desmosomes, and basal lamina.
Soft tissue; Myoepithelioma; Cytology
Toll-like receptors (TLRs) are ancient microbial pattern recognition receptors highly conserved from Drosophila to humans. To investigate if subsets of human dendritic cell precursors (pre-DC), including monocytes (pre-DC1), plasmacytoid DC precursors (pre-DC2), and CD11c+ immature DCs (imDCs) are developed to recognize different microbes or microbial antigens, we studied their TLR expression and responses to microbial antigens. We demonstrate that whereas monocytes preferentially express TLR 1, 2, 4, 5, and 8, plasmacytoid pre-DC strongly express TLR 7 and 9. In accordance with these TLR expression profiles, monocytes respond to the known microbial ligands for TLR2 (peptidoglycan [PGN], lipoteichoic acid) and TLR4 (lipopolysaccharide), by producing tumor necrosis factor (TNF)-α and interleukin (IL)-6. In contrast, plasmacytoid pre-DCs only respond to the microbial TLR9-ligand, CpG-ODNs (oligodeoxynucleotides [ODNs] containing unmethylated CpG motifs), by producing IFN-α. CD11c+ imDCs preferentially express TLR 1, 2, and 3 and respond to TLR 2-ligand PGN by producing large amounts of TNF-α, and to viral double-stranded RNA-like molecule poly I:C, by producing IFN-α and IL-12. The expression of distinct sets of TLRs and the corresponding difference in reactivity to microbial molecules among subsets of pre-DCs and imDCs support the concept that they have developed through distinct evolutionary pathways to recognize different microbial antigens.
immunity,; natural; bacteria; receptors, immunologic; monocytes; cytokines
The NF1 tumor-suppressor gene is frequently inactivated in juvenile myelomonocytic leukemia, and Nf1 mutant mice model this myeloproliferative disorder (MPD). Competitive repopulation assays were performed to quantify the proliferative advantage of Nf1–/– hematopoietic cells in vivo. Nf1 mutant stem cells demonstrated a growth advantage that was greatest in myeloid lineage cells and least pronounced in T lymphocytes. Surprisingly, although low numbers of Nf1-deficient cells consistently outcompeted wild-type cells, levels of chimerism were stable over months of observation, and MPD was not observed unless threshold numbers of mutant cells were injected. These data showing that normal competitor cells can strongly modulate the growth of mutant populations in vivo have general implications for modeling cancer in the mouse. In particular, strains in which cancer-associated mutations are expressed in fields of target cells may not accurately model early events in tumorigenesis because they eliminate the requirement for a mutant clone to outcompete resident normal cells.
An immunohistological study of paraffin wax embedded tissue from three cases of plasmacytoid monocyte neoplasms, using a panel of antibodies which react with fixation resistant leucocyte markers, is reported. This neoplasm was found to have a distinctive antigenic profile, being negative for CD3 and elastase, but positive for CD43 and CD68. This immunological phenotype, coupled with its characteristic morphological features, should facilitate the recognition of this rare neoplasm in routinely processed tissue. Furthermore, the term "plasmacytoid monocyte sarcoma" is proposed to designate it because it is inappropriate to refer to it as a lymphoma. As all cases have been associated with a myeloproliferative disorder (usually an acute or chronic myeloid leukaemia), these tumours probably represent the accumulation in lymphoid tissue of neoplastic cells which have differentiated along the plasmacytoid monocyte pathway.
Rhabdoid tumor, first described in kidneys of infants and children, is an aggressive tumor that has been reported in several extrarenal locations. In this report, we describe the case of a 40-year-old patient with gastric adenocarcinoma composed of histologically well-differentiated glandular areas and focal rhabdoid zones. The rhabdoid component showed typical features such as abundant eosinophilic cytoplasm, eccentric nuclei, prominent nucleoli and intense focal positive immunohistochemical cytoplasmic reaction for vimentin. Recognition of the rhabdoid phenotype in gastrointestinal tract neoplasms is important because this feature is associated with poor prognosis and unresponsiveness to conventional therapy.
Gastric adenocarcinoma; rhabdoid; immunohistochemistry; prognosis
Collecting duct carcinoma (CDC) with a mass of coagulative necrosis is very rare. We report here a case of CDC with extensive geographic coagulative necrosis mimicking anemic infarct with tumor cells embedded around the necrotic foci in a 73-years-old man. Histopathological examination showed that tumor nests near the necrotic foci were arranged as angulated tubules, tubulopapillary and glandular structures. Neoplastic cells had moderate to abundant eosinophilic cytoplasm and large hyperchromatic nuclei with prominent nucleoli as Fuhrman nuclear grade 3 or 4. The tumor cells were positive for pan-Cytokeratin, Vimentin, E-cadherin, CD10, and CK7, confirming the diagnosis as CDC. The patient is still alive 6 months later from nephrectomy, a long time following up is needed to learn the prognosis. Conclusively, morphology from different portions of the lesion, immunohistochemical stain and the combination analysis of the radiological features is essential to make a precise pathological diagnosis of CDC. And CDC should also be distinguished from clear cell renal cell carcinoma, renal medullary carcinoma, urothelial carcinoma with glandular differentiation, renal neuroendocrine tumor, renal epithelioid angiomyolipoma, renal pigmented paraganglioma and renal mesenchymal chondrosarcoma etc.
The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/1264270525975030
Collecting duct carcinoma (CDC); Renal epithelial tumors; Extensive coagulative necrosis; Anemic infarct; Differential diagnosis
Acute lymphoblastic leukemia is predominantly found in children. It is a neoplasm of precursor cells or lymphoblasts committed to either a B- or T-cell lineage. The immature cells in B-acute lymphoblastic leukemia/lymphoma can be small or medium sized with scant or moderate cytoplasm and typically express B-cell markers such as CD19, cytoplasmic CD79a, and TdT without surface light chains. These markers, along with cytogenetic studies, are vital to the diagnosis, classification, and treatment of these neoplasms. We present an unusual case of a precursor B-cell ALL, in an 82-year-old woman, who presented with pancytopenia and widespread lymphadenopathy. The cells show L3 morphology (Burkitt-like lymphoma) with coexpression of TdT and surface light chains in addition to an MYC gene translocation and Philadelphia chromosome.
The aberrant expression of proto-oncogenes is involved in processes that are responsible for cellular proliferation and the inhibition of myeloid differentiation in acute myeloid leukemia (AML). Pituitary Tumor-Transforming gene 1 (PTTG1), an oncogenic transcription factor, is abundantly expressed in various human cancers and hematopoietic malignancies. However, its expression in normal leukocytes and most normal tissues is very low or undetectable. The mechanism by which PTTG1 overexpression modifies myeloid cell development and promotes leukemogenesis remain unclear. To investigate the mechanistic links between PTTG1 overexpression and leukemia cell differentiation, we utilized phorbol 12-myristate 13-acetate (PMA), a well-known agent that triggers monocyte/macrophage differentiation, to analyze the expression patterns of PTTG1 in PMA-induced myeloid differentiation. We found that PTTG1 is down-regulated at the transcriptional level in PMA-treated HL-60 and THP1 cells. In addition, we identified a binding site for a tumor suppressor protein, Kruppel-like factor 6 (KLF6), in the PTTG1 promoter. We found that KLF6 could directly bind and repress PTTG1 expression. In HL-60 and THP1 cells, KLF6 mRNA and protein levels are up-regulated with a concordant reduction of PTTG1 expression upon treatment with PMA. Furthermore, KLF6 knockdown by shRNA abolished the suppression of PTTG1 and reduced the activation of the differentiation marker CD11b in PMA-primed cells. The protein kinase C (PKC) inhibitor and the MAPK/ERK kinase (MEK) inhibitor significantly blocked the potentiation of PMA-mediated KLF6 induction and the down-regulation of PTTG1, indicating that PTTG1 is suppressed via the activation of PKC/ERK/KLF6 pathway. Our findings suggest that drugs that increase the KLF6 inhibition of PTTG1 may have a therapeutic application in AML treatment strategies.
Plasmacytoid adenocarcinoma of the lung has not been reported. Herein reported is the first case of plasmacytoid adenocarcinoma of the lung. A 68-year-old man presented with cough and sputum. X-P and CT demonstrated a large tumor (10 x 10 x 9 cm) in the right upper lobe. CT-guided needle biopsy was performed. The biopsy showed plasmacytoid malignant cells. The malignant cells were small, had eccentrically located nuclei, perinuclear halo, and basophilic cytoplasm. No mucins were observed by mucins stains. Immunohistochemical study showed that the tumor cells were positive for pancytokeratin AE1/3, pancytokeratin CAM5.2, TTF-1, Ki-67 (labeling 70%), CA19-9, and p53. They were negative for neuron specific enolase, CEA, CD45, CD68, chromogranin, synaptophysin, surfactant apoprotein A, CDX-2, κ-chain, λ-chain, KIT, and PDGFRA. Since epithelial markers and adenocarcinoma markers were positive, the pathological diagnosis was plasmacytoid adenocarcinoma of lung. The patient is now treated with chemotherapy.
Lung; plasmacytoid adenocarcinoma; histopathology; immunohistochemistry
In adults, the 2 main types of myelodysplastic/myeloproliferative neoplasms (MDS/MPN) are chronic myelomonocytic leukemia (CMML) and atypical chronic myeloid leukemia (aCML). Both are associated with a poor prognosis. Allogeneic hematopoietic cell transplantation (HCT) is the only known curative treatment modality for these diseases, but data on outcomes following such treatment are limited. We analyzed the outcomes of patients with MDS/MPN after allogeneic HCT.
This retrospective study included 10 patients with MDS/MPN who received allogeneic HCT at Asan Medical Center from 2002 to 2010. Of these 10 patients, 7 had CMML, 2 had aCML, and 1 had unclassifiable MDS/MPN. Five patients received a myeloablative conditioning (MAC) regimen (busulfan-cyclophosphamide), and 5 received reduced-intensity conditioning (RIC) regimen.
Neutrophil engraftment was achieved in all patients. After a median follow-up of 47.5 months among surviving patients, 4 had relapsed and 5 had died. There was only 1 treatment-related death. The 5-year rates of overall, relapse-free, and event-free survival were 42.2%, 51.9%, and 46.7%, respectively. Relapse was the leading cause of treatment failure, and all relapses were observed in patients who had received RIC and who did not develop chronic graft-versus-host disease.
Allogeneic HCT can induce durable remission in patients with MDS/MPN, but RIC cannot replace MAC in patients eligible for myeloablative treatments.
MDS/MPN; Allogeneic HCT; Reduced-intensity; Relapse