Riccardo Valdez

Pten dependence distinguishes haematopoietic stem cells from leukaemia-initiating cells

Recent advances have highlighted extensive phenotypic and functional similarities between normal stem cells and cancer stem cells. This raises the question of whether disease therapies can be developed that eliminate cancer stem cells without eliminating normal stem cells. Here we address this issue by conditionally deleting the Pten tumour suppressor gene in adult haematopoietic cells. This led to myeloproliferative disease within days and transplantable leukaemias within weeks. Pten deletion also promoted haematopoietic stem cell (HSC) proliferation. However, this led to HSC depletion via a cell-autonomous mechanism, preventing these cells from stably reconstituting irradiated mice. In contrast to leukaemia-initiating cells, HSCs were therefore unable to maintain themselves without Pten. These effects were mostly mediated by mTOR as they were inhibited by rapamycin. Rapamycin not only depleted leukaemia-initiating cells but also restored normal HSC function. Mechanistic differences between normal stem cells and cancer stem cells can thus be targeted to deplete cancer stem cells without damaging normal stem cells.

CD117 (KIT receptor) expression in Merkel cell carcinoma

The KIT receptor tyrosine kinase (CD117 antigen) is found in a variety of normal tissue cell types and in several malignant tumors, including acute myeloid leukemia. We recently encountered two tumors initially suspected as acute myeloid leukemia cutis and expressing CD117 that showed punctate positivity for cytokeratin 20 diagnostic for Merkel cell carcinoma. We evaluated 20 additional cases of MCC and found that 21 of 22 tumors (95%) expressed CD117. Intensity of CD117 expression did not appear to correlate with aggressive behavior. While the function of the KIT receptor in MCC is not known, its pathogenic role in other malignant neoplasms suggests the possibility of a similar role in MCC.

Lymphocytic Mastitis and Diabetic Mastopathy: A Molecular, Immunophenotypic, and Clinicopathologic Evaluation of 11 Cases

Lymphocytic mastitis and diabetic mastopathy are uncommon fibroinflammatory breast diseases. The lesions seen in these entities are unique in that the associated lymphoid infiltrates are composed of predominantly B cells. In addition, B-cell lymphoepithelial lesions, a finding commonly associated with extranodal marginal zone B-cell/mucosa-associated lymphoid tissue (MALT) lymphomas, are also often present in lymphocytic mastitis and diabetic mastopathy. Although the clinical and immunomorphologic features are well characterized, the clonality of the B-cell infiltrate and the lymphomatous potential of lymphocytic mastitis and diabetic mastopathy have not been emphasized in the literature. We evaluated 11 cases of lymphocytic mastitis/diabetic mastopathy for immunoglobulin heavy chain gene rearrangement and correlated the findings with all available clinical data. A longstanding history of Type I diabetes mellitus was present in seven patients. One nondiabetic patient had Sjogren’s syndrome, and two patients had no history of diabetes mellitus or other autoimmune disease. Clinical data were unavailable for one patient. B-cell–predominant lymphoid infiltrates were seen in all cases, and B-cell lymphoepithelial lesions were found in five. No evidence of a B-cell clone was found in any of the 11 cases by appropriately controlled immunoglobulin heavy chain gene rearrangement studies, and none of the patients developed lymphoma during follow-up intervals ranging from 2–126 months. These findings suggest that despite the presence of B-cell–predominant lymphoid infiltrates and lymphoepithelial lesions, lymphocytic mastitis and diabetic mastopathy do not appear to be associated with an increased risk for lymphoma.

Waldenström Macroglobulinemia Caused by Extranodal Marginal Zone B-Cell Lymphoma A Report of Six Cases

Waldenström macroglobulinemia (WM) and its associated hyperviscosity syndrome (HVS) are generally caused by lymphoplasmacytoid lymphoma or other small B-cell lymphoproliferative disorders. WM associated with extranodal marginal zone B-cell-mucosa-associated lymphoid tissue lymphoma (EMZL/MALT-type) has not been emphasized. We describe 4 men and 2 women (age, 40-79 years) with clinical and laboratory manifestations of WM and EMZL/MALT-type involving one or more sites: lung, pericardium/pleura, ocular adnexa, nasopharynx, minor salivary gland, glossopharyngeal fold, skin, and stomach. The following immunophenotypic patterns were observed: CD20+, 6; CD43+, 3; kappa light chain restriction, 5; and lambda light chain restriction, 1. All were negative for CD5, CD10, and cyclin D1 expression. A clonal paraproteinemia was present in each (IgM kappa, 4; IgM lambda, 1; biclonal IgM kappa/IgA kappa, 1). All 4 patients tested had elevated plasma viscosity; clinical HVS occurred in 3, and 2 required emergency plasmapheresis. These findings suggest that EMZL/MALT-type can cause WM and that the laboratory evaluation of EMZL/MALT-type should include serum protein electrophoresis/immunofixation, and plasma viscosity measurements and urine immunofixation in select cases. EMZL/MALT-type should be considered in the differential diagnosis in patients with clinicopathologic features of WM.

Cerebrospinal Fluid Involvement in Mantle Cell Lymphoma

Mantle cell lymphoma (MCL) is an aggressive neoplasm that is incurable by standard therapy. Patients often present with high-stage disease (Stages III–IV) and frequently have involvement at multiple extranodal sites. Although the gastrointestinal tract, spleen, lung, pleura, bone marrow, and peripheral blood are among the most commonly involved tissues, MCL may also disseminate to so-called sanctuary sites including the central nervous system. Despite this, current clinical evaluations do not routinely include assessment of the cerebrospinal fluid (CSF) for lymphomatous infiltrates at presentation, and moreover, only few authors have specifically examined CSF involvement in MCL. In this study, we reviewed the medical records of 108 patients with MCL seen at three centers over a 5-year period to determine the rate of CSF sampling and the frequency of CSF involvement by MCL. The clinical and cytologic characteristics associated with CSF involvement were also studied. Central nervous system (CNS) signs and/or symptoms prompted CSF sampling in 25/108 patients (23%). Specific radiographic abnormalities were present in 9/25 patients (36%). CSF involvement by MCL was identified in 10 of the 25 CSF-sampled patients (40%) by morphology (3 patients), flow cytometry alone (1 patients), or both (6 patients). The CSF-positive cases included two blastoid variants. The CSF cytology of the nine morphologically positive cases was pleomorphic, and prominent cytoplasmic granules were observed in two cases. The overall rate of CSF involvement by MCL among the cohort was 9%, which is comparable to that reported in other selected studies examining this issue.

Site-specific morphologic differences in extranodal marginal zone B-cell lymphomas.

CONTEXTnLymphoepithelial lesions (LELs) are a useful diagnostic feature of extranodal marginal zone B-cell lymphoma (EMZL); however, there is scant literature comparing their frequency and morphology at various sites.nnnOBJECTIVEnTo evaluate any diagnostically useful, site-specific, morphologic patterns in EMZLs.nnnDESIGNnIn this retrospective review, we evaluated 136 EMZLs from different sites for LEL pattern and other pathologic differences, including CD43 coexpression and plasma cell component features.nnnRESULTSnProminent and destructive LELs were most common in salivary and thyroid gland cases, and LELs were rare to absent in breast, skin, and ocular adnexa cases. An LEL pattern with lymphocytes stuffing glandular lumina was seen in lung, thyroid, and salivary gland cases. Monoclonal plasma cells were most common in breast, upper aerodigestive tract, skin, and salivary gland cases. CD43 coexpression was seen in 36% of cases, most commonly in salivary gland, stomach, and upper aerodigestive tract.nnnCONCLUSIONSnThe relative importance of LEL pattern, CD43 coexpression, and clonal plasma cell component in EMZLs is site-dependent, and the differences may aid in the diagnosis of EMZLs at different anatomic sites.

Acute megakaryocytic leukemia presenting as hypercalcemia with skeletal lytic lesions

Abstract:u2002 Acute megakaryocytic leukemia (AML M7) is a rare type of acute myelogenous leukemia in adults, commonly presenting with myelofibrosis. This report describes a case of a 32‐yr‐old male who presented with hypercalcemia and bony lytic lesions, in the absence of myelofibrosis. The diagnosis of AML M7 should be considered in a patient with pancytopenia, lytic lesions and hypercalcemia.

Fascin expression in diffuse large B-cell lymphoma, anaplastic large cell lymphoma, and classical hodgkin lymphoma

CONTEXTnFascin is an actin-bundling protein involved in the formation of dendritic processes. Fascin is a sensitive marker for classical Reed-Sternberg cells and has a high negative predictive value for diagnosis of classical Hodgkin lymphoma (CHL). Fascin has been used to distinguish CHL from non-Hodgkin lymphoma. Recently, it was shown that fascin might not help differentiate CHL from anaplastic large cell lymphoma (ALCL). Moreover, fascin has not been extensively studied in the context of other large cell lymphomas.nnnOBJECTIVEnTo analyze fascin expression in diffuse large B-cell lymphoma (DLBCL) and also reexamine its usefulness in discriminating CHL from ALCL.nnnDESIGNnFormalin-fixed, paraffin-embedded tissue samples from 41 cases of DLBCL, 30 cases of CHL, and 30 cases of ALCL were analyzed. Fascin expression was compared across each type of lymphoma with additional correlation between fascin positivity and ALK-1 expression in ALCL performed.nnnRESULTSnOnly 6 (14.6%) of 41 cases of DLBCL stained positively for fascin, with most neoplastic large cells exhibiting a weak staining pattern. Fifteen (50%) of 30 cases of ALCL showed positivity for fascin, with most large cells staining strongly. All 30 cases of CHL demonstrated intense positive staining. Sixty percent of fascin-positive ALCLs were positive for ALK-1, while 66.7% of fascin-negative ALCLs were positive for ALK-1.nnnCONCLUSIONSnFascin is highly sensitive for CHL and has a very high negative predictive value (100% in this series) for distinguishing CHL from DLBCL or ALCL. However, the specificity and positive predictive value for fascin are much higher in distinguishing CHL from DLBCL than in distinguishing CHL from ALCL. Expression of fascin appears more useful in the differential diagnosis of CHL versus DLBCL than in the differential diagnosis of CHL versus ALCL.

Nodular Lymphocyte Predominant Hodgkin Lymphoma An Immunophenotypic Reappraisal Based on a Single-Institution Experience

In our experience, certain commonly cited immunophenotypic features of nodular lymphocyte predominant Hodgkin lymphoma (NLPHL) are not encountered in day-to-day practice. We reviewed 60 cases of NLPHL (18 women, 42 men; median age, 34 years) to discern immunophenotypic features from a large, single-institution cohort. All cases contained lymphocytic and histiocytic (L&H) cells. These cells expressed CD20 in 98% (59/60), CD79a (usually faint) in 87% (27/31), CD30 in 7% (4/59), epithelial membrane antigen in 21% (12/56), bcl-2 in 5% (2/41), and bcl-6 in 83% (30/36) of cases. CD10 was negative in all 36 cases studied; 100% of cases (55/55) demonstrated CD3+ rosettes. Although CD57+ T cells were common within the background infiltrate, CD57+ rosettes were seen in only 48% of cases (15/31) and were rare when encountered. Based on these patterns, we conclude that bcl-2 and bcl-6 may be useful additions to the immunophenotypic analysis of NLPHL, but that the diagnostic usefulness of epithelial membrane antigen and CD57 rosettes may have been overemphasized in previous reports.

ALK-Positive Anaplastic Large Cell Lymphoma With Primary Bone Involvement in Children

We describe the clinical, radiologic, and pathologic features of primary bone anaplastic large cell lymphoma (ALCL) in 3 boys. Radiologic imaging showed lytic lesions involving sacrum, femur, or rib. Bone was the only site of disease in 2 cases; an associated partial lymph node was involved in case 3. Differential diagnoses included osteomyelitis and small round cell tumors of childhood, particularly Ewing sarcoma. Preoperatively, ALCL was not a diagnostic consideration in any case. Two cases showed classic large pleomorphic cells; 1 showed a composite pattern with a distinct small cell component and the more typical large cell type. Neoplastic cells in all cases showed strong CD30 and anaplastic lymphoma kinase expression with relatively weak epithelial membrane antigen positivity. Cytotoxic granule protein was expressed in 2 cases. All cases showed unusually strong expression of neuron-specific enolase (NSE). Two patients were disease-free at last follow-up (15 months and 11 years); 1 patient died of disseminated disease within a year of diagnosis. ALCL should be considered a diagnostic possibility when evaluating neoplastic bone lesions in children. Although expression of NSE in ALCL has not been emphasized in the literature, it is worth noting because it may pose a diagnostic pitfall.