Christine Beham-Schmid

Specific cutaneous infiltrates in patients with myelogenous leukemia: a clinicopathologic study of 26 patients with assessment of diagnostic criteria.

BACKGROUND Few recent studies have analyzed the clinicopathologic features of specific cutaneous manifestations of myelogenous leukemia in a large number of patients. OBJECTIVE We characterize the clinical and histopathologic spectrum of specific cutaneous manifestations in acute (AML) and chronic (CML) myelogenous leukemia, ascertain further diagnostic criteria, and examine current prognosis. METHODS Thirty-six lesions of specific cutaneous infiltrates from 26 patients with myelogenous leukemia (AML: 17 patients; M:F = 1:2.4; mean age: 52.6 years; AML-French-American-British [FAB] classification subtypes:M1 = 1, M2 = 3, M4 = 8, M5 = 5. CML = 9 patients; M:F = 4.5:1; mean age: 60.6 years) were retrospectively collected for the study. RESULTS Cutaneous manifestations presented as solitary or multiple reddish to violaceous papules, plaques, and nodules (17 lesions), or as a generalized erythematous maculopapular eruption (9 lesions). Concurrent extramedullary involvement in other peripheral sites (eg, gums, pharynx, orbits) was observed in 10 patients. Histopathologically, lesions revealed nodular/diffuse infiltrates, often with perivascular and periadnexal accentuation, sparing of the upper papillary dermis, and prominent single arraying of neoplastic cells between collagen bundles. Extension to the subcutis was noted in all deep biopsy specimens (26 lesions). Cytomorphologically, medium to large-sized mononuclear cells (myeloblasts and atypical myelocytes) predominated in AML-M1 and M2, whereas M4 and M5 mainly showed small, medium-sized, or large mononuclear cells with slightly eosinophilic cytoplasm and indented, bi-lobular, or kidney-shaped nuclei (atypical monocytoid cells). In CML, either a variable mixture of mature and immature cells of the granulocytic series (myelocytes, metamyelocytes, eosinophilic metamyelocytes, and neutrophils) or a rather monomorphous infiltrate of mononuclear cells were found. Staining for naphthol AS-D chloroacetate-esterase (NASD) was positive in 24 of 36 lesions (66.6%; AML: 16; CML: 8). Immunohistochemical analysis on paraffin sections using a large panel of antibodies (16 lesions: AML: 13; CML: 3) showed strong reactivity for LCA (CD45), lysozyme, myeloperoxidase (MPD), LN2 (CD74), HLA-DR, and MT1 (CD43) in the majority of cases, and variable staining for monocyte/macrophage markers (KP1/CD68, PGM1/CD68, Mac387, Ki-M1p). The neuronal cell adhesion molecule (NCAM) marker CD56 was reactive in 2 cases of CML, but negative in all cases of AML. MIB1(Ki67) stained 20% to 80% of neoplastic cells. CD34, CD15, CD20, and CD3 were negative in all cases. No correlation between histochemical/immunohistochemical features with type of leukemia or FAB-subtype of AML was observed. All patients with CML and AML with adequate follow-up died within 24 months after onset of skin lesions (mean survival, AML: 7.6 months; CML: 9.4 months). CONCLUSION Specific cutaneous lesions in AML and CML show distinctive clinicopathologic features that allow diagnosis in most cases. Immunohistochemistry on routinely fixed, paraffin-embedded tissue sections provides useful adjunctive information. Simultaneous expression of lysozyme, MPD, CD45, CD43, and CD74 militates in favor of a diagnosis of specific cutaneous infiltrate of myelogenous leukemia. Pitfalls in immunohistologic diagnosis mainly include lack of expression of some myeloid markers (lysozyme, MPD), and aberrant expression of T-cell markers (eg, CD45RO). Regardless of type of myelogenous leukemia, onset of specific skin manifestations correlates with an aggressive course and short survival.

Treatment of Extranodal Marginal Zone B-Cell Lymphoma of Mucosa-Associated Lymphoid Tissue Type With Cladribine: A Phase II Study

PURPOSE As chemotherapy has not been extensively studied in patients with lymphoma of the mucosa-associated lymphoid tissue (MALT), we initiated a prospective study to evaluate the activity of the nucleoside analog cladribine (2-chlorodeoxyadenosine [2-CdA]) in this disease. PATIENTS AND METHODS Patients with histologically verified MALT-type lymphoma were enrolled. 2-CdA was administered at a dose of 0.12 mg/kg body weight on 5 consecutive days, as a 2-hour infusion. Cycles were repeated every 4 weeks for a maximum of six cycles. RESULTS Nineteen patients with gastric and seven patients with extragastric MALT lymphoma were enrolled. All patients were chemotherapy-naive, and two had been locally irradiated before systemic relapse of the lymphoma. A total of 102 cycles was administered to our patients (median number of cycles per patient, four). All 25 assessable patients responded to treatment: 21 patients (84%) achieved complete remission (CR) and four patients achieved partial remission. All patients (100%) with gastric presentation, but only three patients (43%) with extragastric presentation, achieved CR. Toxicities were moderate and mainly hematologic and required dose reduction and/or premature discontinuation of therapy in only three cases. Two patients died from vascular events, one shortly after the first cycle because of myocardial infarction and the other from stroke 3 months after the second course. Three patients relapsed after 13, 18, and 22 months and one patient showed progressive disease after 15 months. At present, 24 patients are alive at a median follow-up time of 32 months. CONCLUSION Our data demonstrate that 2-CdA is highly effective in inducing CR in 84% of patients with MALT-type lymphoma.

Nasopharyngeal angiofibroma: true neoplasm or vascular malformation?

Summary: Nasopharyngeal angiofibromas (NA) are rare tumor‐like lesions characterized by architecturally irregular vessels set in a fibrous stroma. The unique morphology, the strong predilection for male adolescents, and the uncertainty about its etiology contributes to significant confusion regarding the classification of NA, which still has not been solved today. Based on immunohistochemical and electron microscopic examinations, we demonstrate in detail the various unusual vascular architectural features of NA. They represent discontinuous vascular basal laminae, focal lack of pericytes, and pronounced irregularity of the smooth muscle layers. In thick smooth muscle layers and pads, the orientation of muscle cells is frequently disturbed, and the individual cells differ in size and shape. Occasionally, the muscle layers disperse peripherally into individual cells, creating the impression of vessel‐independent smooth muscle cells within the stroma. The summation of all morphological irregularities demonstrated in this paper allows the conclusion that NA represent vascular malformations.

Epigenetic and in vivo comparison of diverse MSC sources reveals an endochondral signature for human hematopoietic niche formation

In the last decade there has been a rapid expansion in clinical trials using mesenchymal stromal cells (MSCs) from a variety of tissues. However, despite similarities in morphology, immunophenotype, and differentiation behavior in vitro, MSCs sourced from distinct tissues do not necessarily have equivalent biological properties. We performed a genome-wide methylation, transcription, and in vivo evaluation of MSCs from human bone marrow (BM), white adipose tissue, umbilical cord, and skin cultured in humanized media. Surprisingly, only BM-derived MSCs spontaneously formed a BM cavity through a vascularized cartilage intermediate in vivo that was progressively replaced by hematopoietic tissue and bone. Only BM-derived MSCs exhibited a chondrogenic transcriptional program with hypomethylation and increased expression of RUNX3, RUNX2, BGLAP, MMP13, and ITGA10 consistent with a latent and primed skeletal developmental potential. The humanized MSC-derived microenvironment permitted homing and maintenance of long-term murine SLAM(+) hematopoietic stem cells (HSCs), as well as human CD34(+)/CD38(-)/CD90(+)/CD45RA(+) HSCs after cord blood transplantation. These studies underscore the profound differences in developmental potential between MSC sources independent of donor age, with implications for their clinical use. We also demonstrate a tractable human niche model for studying homing and engraftment of human hematopoietic cells in normal and neoplastic states.

Keratoacanthoma: a clinically distinct variant of well differentiated squamous cell carcinoma.

Summary Keratoacanthomas are distinct skin lesions that occur most often as solitary tumors in sun-exposed areas in elderly, fair-skinned patients. Clinically, these tumors are characterized by a rapid onset and regression within months. Keratoacanthomas display distinct histological features including a keratin-filled crater lined by a proliferating squamous epithelium. Cytologically, there may be overlap with classical well differentiated squamous cell carcinoma. Rarely, otherwise typical keratoacanthomas show intravascular and perineural invasion and lymph node metastases. Keratoacanthomas should, therefore, be considered to be a clinically distinct variant of well differentiated squamous cell carcinoma capable of spontaneous regression. This view is supported by their common etiology, occasional concurrent occurrence, and a multitude of studies revealing no substantial differences between these two lesions. Regression is immunologically mediated and activated by a variety of molecular mechanisms. Considering the common nature of keratoacanthomas and well differentiated squamous cell carcinomas, and the lack of any features predicting prognosis, surgical excision of keratoacanthoma is advisable.

Common alterations in gene expression and increased proliferation in recurrent acute myeloid leukemia.

Recurrent disease following high-dose chemotherapy is a major problem in patients with acute myeloid leukemia (AML). To identify its characteristics, we performed expression profiling in blasts from untreated AML and relapse, using a specific cDNA microarray comprising 4128 genes generated by cDNA subtraction supplemented with cancer-associated genes. Expression analysis of 18 AML bone marrow specimens showed that recurrent AML is commonly associated with the mRNA expression changes in a set of 58 genes. Increased cellular proliferation was indicated by the overexpression of the transferrin receptor, proliferating cell nuclear antigen, and G1 cyclins. An immunohistochemical study for Ki-67-positive blasts in 18 paired bone marrow biopsy samples confirmed a highly significant (P<0.0001) increase in the proliferation fraction at relapse. In addition, we found enhanced activation of the RAF/MEK/ERK cascade as mRNAs of MKP-1, c-jun, c-fos, and egr-1 were significantly increased at relapse. Immunohistochemistry and immunoblotting analyses for biphosphorylated ERK1/2 protein provide additional evidence for enhanced activation of the RAF/MEK/ERK pathway. The degree of increase is significantly correlated with the increased proliferation. Furthermore, the genes identified provide a rationale for further studies on predictive diagnosis and therapeutic intervention.

Monoclonal γ-T-Cell Receptor Rearrangement in Vulvar Lichen Sclerosus and Squamous Cell Carcinomas

Risk factors for vulvar squamous cell carcinoma (SCC) are human papilloma virus (HPV) infections and lichen sclerosus (LS). The significance of monoclonal γ-T-cell receptor (γ-TCR) rearrangement in the lymphoid infiltrate of LS and the consequence for vulvar carcinogenesis is unknown. One hundred sixty-one biopsies of vulvar LS and SCC, with and without LS, were examined for monoclonal γ-TCR rearrangement and HPV16 expression, and for the expression of B- and T-cell markers and fascin. Monoclonal γ-TCR rearrangement was identified in 8 of 17 patients with LS and 11 of 21 patients with SCC arising in LS with only occasional HPV16 DNA detection. None of the 19 SCC without LS showed monoclonal γ-TCR rearrangement, but 14 of 19 patients had strong HPV16 detection. The lichenoid infiltrate of LS with germline configuration consisted predominantly of T cells (CD8 > CD4), along with numerous B cells. However, in biopsies with monoclonally rearranged γ-TCR, CD4-positive T cells dominated along with B cells and fascin-positive cells in the lichenoid infiltrate and in deeply located lymphocyte aggregates (LAs). These LAs additionally contained fascin-positive dendritic cells with only individual CD8, CD57, and granzyme-positive cells. LAs in biopsies with germline configuration demonstrated numerous T cells (CD8 >CD4), but only single peripheral B cells, CD57, and fascin-positive lymphocytes. Our data suggest that monoclonal γ-TCR rearrangement is characteristic for and limited to LS and SCC arising in LS, raising the question for a LS-associated antigen. We interpret B cells, CD4-positive T cells, and fascin-expressing dendritic cells within LS as a cellular immune response to antigen or proliferating T-cell clones. The resulting local immune dysregulation in LS may provide a permissive environment for the development of a SCC.

Primary extramedullary plasmacytoma: similarities with and differences from multiple myeloma revealed by interphase cytogenetics

Primary extramedullary plasmacytoma and multiple myeloma show similar chromosomal alterations, as detected by fluorescence in situ hybridization. Primary extramedullary plasmacytoma is an indolent neoplasm that infrequently converts to multiple myeloma. Since cytogenetic data on extramedullary plasmacytoma are lacking, we studied 38 cases of this type of neoplasm by fluorescence in situ hybridization. Fourteen cases (37%) contained IGH breaks, including six with a t(4;14) translocation. No translocations t(11;14), t(14;16), t(8;14), nor breaks involving MALT1, BCL6 or FOXP1 were found. Loss of 13q (40%), as well as chromosomal gains (82%) were common. There was no correlation between chromosomal alterations and clinical features or local relapse. Cytogenetically, extramedullary plasmacytoma and multiple mueloma are closely related. However, the distribution of IGH translocation partners, with the notable absence of t(11;14), is different. Key words: extramedullary plasmacytoma, multiple myeloma, cytogenetics, IGH translocation, fluorescence in situ hybridization.

Trichoblastic Carcinoma (“Malignant Trichoblastoma”) with Lymphatic and Hematogenous Metastases

We report an aggressively behaving malignant trichogenic tumor arising in a trichoblastoma (TB) with widespread lymphatic and hematogenous metastases in a 55-year-old man with a concomitant B-cell chronic lymphocytic leukemia. The primary tumor had been present and unchanged for as long as 40 years before excision. Typical trichogenic TB with dystrophic calcification and even ossification was still present peripheral to the malignant transformation. The malignant neoplasm consisted of basaloid cells, spindle cells arranged in fascicles and densely packed rounded nests or “cell balls.” The metastases consisted of immature basaloid cells and cell balls, and the recurrences became successively more undifferentiated. The residual TB reacted with antibodies to cytokeratin (CK) 6, 8, 14, and 17 and focally to S-100; the malignant primary tumor reacted uniformly with antibodies to vimentin and only focally with antibodies to CK and S-100. The metastatic tumor had lost epidermal CK expression but maintained expression of S-100 in paraffin-embedded tissues. Trichoblastic differentiation was confirmed in frozen tissues with antibodies to hair keratins. No expression of p53 or bcl-2 was identified, but p-glycoprotein (MDR-1 gene related) was expressed by primary and metastatic tumor cells. We believe that this neoplasm is best classified as a trichoblastic carcinoma arising in a TB in association with a B-cell chronic lymphocytic leukemia. This case illustrates that TBs have the potential for malignant transformation and aggressive behavior.

The derived neutrophil to lymphocyte ratio is an independent prognostic factor in patients with diffuse large B-cell lymphoma.

Background:With growing evidence on the role of inflammation in cancer biology, the systemic inflammatory response has been postulated as having prognostic significance in a wide range of different cancer types. Recently, the derived neutrophil to lymphocyte ratio (dNLR) has been proposed as an easily determinable prognostic factor in cancer patients. Nevertheless, its prognostic significance in diffuse large B-cell lymphoma (DLBCL) patients has never been explored.Methods:Data from 290 consecutive DLBCL patients, diagnosed between 2004 and 2013 at a single Austrian centre, were evaluated retrospectively. The prognostic influence of the dNLR and other clinico-pathological factors including age, lactate dehydrogenase, cell of origin category and Ann Arbor stage on 5-year overall- (OS) and disease-free (DFS) survival was studied by Kaplan–Meier curves. To evaluate the independent prognostic relevance of dNLR, univariate and multivariate Cox regression models were applied.Results:An independent significant association between high dNLR and poor clinical outcome in multivariate analysis for OS (HR=2.02, confidence interval (CI) 95%=1.17–3.50, P=0.011), as well as DFS (HR=2.15, CI 95%=1.04–4.47, P=0.038), was identified.Conclusion:In the present study, we showed that a high dNLR at diagnosis of DLBCL represents an independent poor prognostic factor for clinical outcome. Our data encourage the further validation of this easily available parameter in prospective studies and as a potential stratification tool in clinical trials.