Giorgio Alberto Croci

Prevalence and clinical significance of the MYD88 (L265P) somatic mutation in Waldenstrom's macroglobulinemia and related lymphoid neoplasms.

A study has shown that MYD88 (L265P) is a recurring somatic mutation in Waldenströms macroglobulinemia (WM). We developed an allele-specific polymerase chain reaction (PCR) for this mutation, and analyzed bone marrow or peripheral blood samples from 58 patients with WM, 77 with IgM monoclonal gammopathy of undetermined significance (IgM-MGUS), 84 with splenic marginal zone lymphoma (SMZL), and 52 with B-cell chronic lymphoproliferative disorders (B-CLPD). MYD88 (L265P) was detected in 58/58 (100%) patients with WM, 36/77 (47%) with IgM-MGUS, 5/84 (6%) with SMZL, and 3/52 (4%) with B-CLPD. Compared to IgM-MGUS patients with wild-type MYD88, those carrying MYD88 (L265P) showed significantly higher levels of IgM (P < .0001) and presented Bence-Jones proteinuria more frequently at diagnosis (P = .002). During follow-up, 9 patients with IgM-MGUS progressed to WM or to marginal zone lymphoma. Using a case-control approach, the risk of evolution of patients carrying MYD88 (L265P) was significantly higher than that of patients with wild-type MYD88 (odds ratio 4.7, 95% confidence interval 0.8 to 48.7, P = .047). These findings indicate that the allele-specific PCR we developed is a useful diagnostic tool for patients with WM or IgM-MGUS. In this latter condition, MYD88 (L265P) is associated with greater disease burden and higher risk of disease progression, and the mutation may therefore also represent a useful prognostic marker.

Epigenetic silencing of miR-26A1 in chronic lymphocytic leukemia and mantle cell lymphoma: Impact on EZH2 expression.

ABSTRACT Downregulation of miR26A1 has been reported in various B-cell malignancies; however, the mechanism behind its deregulation remains largely unknown. We investigated miR26A1 methylation and expression levels in a well-characterized series of chronic lymphocytic leukemia (CLL) and mantle cell lymphoma (MCL). From 450K methylation arrays, we first observed miR26A1 (cg26054057) as uniformly hypermethylated in MCL (n = 24) (all >75%), while CLL (n = 18) showed differential methylation between prognostic subgroups. Extended analysis using pyrosequencing confirmed our findings and real-time quantitative PCR verified low miR26A1 expression in both CLL (n = 70) and MCL (n = 38) compared to normal B-cells. Notably, the level of miR26A1 methylation predicted outcome in CLL, with higher levels seen in poor-prognostic, IGHV-unmutated CLL. Since EZH2 was recently reported as a target for miR26A1, we analyzed the expression levels of both miR26A1 and EZH2 in primary CLL samples and observed an inverse correlation. By overexpression of miR26A1 in CLL and MCL cell lines, reduced EZH2 protein levels were observed using both Western blot and flow cytometry. In contrast, methyl-inhibitor treatment led to upregulated miR26A1 expression with a parallel decrease of EZH2 expression. Finally, increased levels of apoptosis were observed in miR26A1-overexpressing cell lines, further underscoring the functional relevance of miR26A1. In summary, we propose that epigenetic silencing of miR26A1 is required for the maintenance of increased levels of EZH2, which in turn translate into a worse outcome, as shown in CLL, highlighting miR26A1 as a tumor suppressor miRNA.

Successful treatment of a classic Hodgkin lymphoma-type post-transplant lymphoproliferative disorder with tailored chemotherapy and Epstein-Barr virus-specific cytotoxic T lymphocytes in a pediatric heart transplant recipient.

CHL type is the least common major form of EBV‐related PTLD but rarely occurs in pediatric recipients; development of CHL subsequent to other PTLD subtypes in the same transplant recipient is even more unusual. Because of its rarity, indications on the best treatment strategy are limited. Patients have been mostly treated with standard HL chemotherapy/radiotherapy, and prognosis seems more favorable than other monomorphic PTLDs. Herein, we describe a pediatric case of EBV‐associated, stage IV‐B, CHL arising in a heart allograft recipient eight yr after diagnosis of B‐cell polymorphic PTLD. The patient was successfully treated with adjusted‐dose HL chemotherapy and autologous EBV‐specific CTL, without discontinuation of maintenance immunosuppression. At two yr from therapy completion, the patient is in CR with stable organ function. With this strategy, it may be possible to reproduce the good prognostic data reported for CHL‐type PTLD, with decreased risk of organ toxicity or rejection.

Primary cutaneous B‐cell lymphoma other than marginal zone: clinicopathologic analysis of 161 cases: Comparison with current classification and definition of prognostic markers

Categorization of primary cutaneous B‐cell lymphomas (PCBCL) other than marginal zone (MZL) represents a diagnostic challenge with relevant prognostic implications. The 2008 WHO lymphoma classification recognizes only primary cutaneous follicular center cell lymphoma (PCFCCL) and primary cutaneous diffuse large B‐cell lymphoma, leg type (PCDLBCL‐LT), whereas the previous 2005 WHO/EORTC classification also included an intermediate form, namely PCDLBCL, other. We conducted a retrospective, multicentric, consensus‐based revision of the clinicopathologic characteristics of 161 cases of PCBCL other than MZL. Upon the histologic features that are listed in the WHO classification, 96 cases were classified as PCFCCL and 25 as PCDLBCL‐LT; 40 further cases did not fit in the former subgroups in terms of cytology and/or architecture, thus were classified as PCDLBCL, not otherwise specified (PCDLBCL‐NOS). We assigned all the cases a histogenetic profile, based on the immunohistochemical detection of CD10, BCL6, and MUM1, and a “double hit score” upon positivity for BCL2 and MYC. PCDLBCL‐NOS had a clinical presentation more similar to PCFCCL, whereas the histology was more consistent with the picture of a diffuse large B‐cell lymphoma, as predominantly composed of centroblasts but with intermixed a reactive infiltrate of small lymphocytes. Its behavior was intermediate between the other two forms, particularly when considering only cases with a “non‐germinal B‐cell” profile, whereas “germinal center” cases resembled PCFCCL. Our data confirmed the aggressive behavior of PCDLBC‐LT, which often coexpressed MYC and BCL2. The impact of single factors on 5‐year survival was documented, particularly histogenetic profile in PCDLBCL and BCL2 translocation in PCFCCL. Our study confirms that a further group—PCDLBCL‐NOS—exists, which can be recognized through a careful combination of histopathologic criteria coupled with adequate clinical information.

Cutaneous blastic plasmacytoid dendritic cell neoplasm: successful palliative treatment with oral prednisone in an elderly patient.

no specific reactivity for epidermal proteins. These findings may mean that autoimmunity mediated by a monoclonal IgA-j antibody against an unknown epidermal antigen may exhibit an affinity that is not enough to be detected by ELISA or immunoblotting. Another possibility is that the unknown antigen may be modified during the molecular procedure, giving rise to negative results. Further investigations are needed to define the specificity and significance of these results.

An unusual case of transient neonatal pustular melanosis: a diagnostic puzzle

A newborns skin may exhibit a variety of changes during the first weeks of life, and rashes are extremely common in the neonatal period, representing a significant source of parental concern. In particular, a variety of skin eruptions can present as pustules. Most of them are innocuous and self-limiting, while others can be the manifestation of an infectious disease or even indicative of serious underlying disorders. Transient neonatal pustular melanosis is an uncommon vesiculopustular rash characterized by small pustules on a non-erythematous base, noted at birth or during the first day of life, without systemic symptoms. The lesions rupture spontaneously, leaving hyperpigmented macules that usually fade within few weeks. Clinical recognition of this disease can help physicians avoid unnecessary diagnostic testing and treatment for infectious etiologies because no specific therapy is recommended. The clinical aspect and time of onset are generally sufficient to make the correct diagnosis. Nevertheless, peculiar clinical presentations may require additional work-up to rule out life-threatening conditions, and dermatological consultation and histological examination are required for the final diagnosis. Conclusion: We report an exceedingly unusual presentation of transient neonatal pustular melanosis, suggesting the importance of a systematic diagnostic approach to allow a confident recognition of this benign condition.

Cutaneous involvement by post-polycythemia vera myelofibrosis

A 69-year-old man presented with multiple skin lesions scattered across his thorax and abdomen that had appeared 3 months earlier. He had a 20-year history of polycythemia vera with homozygosity for JAK2 V617F and was treated with hydroxyurea and aspirin since diagnosis. Skin lesions were macular to papulonodular, reddish to purple, up to 3 cm in diameter (Image 1A), and hard on palpation. The patient denied they were itchy or painful. Apart from that, physical examination was notable only for mild hepatosplenomegaly. Blood cell count showed leukocytosis (WBC 14.3 3 10/L) with hemoglobin concentration and platelet count within normal limits. Peripheral blood smear was characterized by red cell anisopoikilocytosis with dacryocytosis, and leukoerythroblastic picture with 2% micromegakaryocytes and 1% blasts. Ultrasonografy showed that spleen major diameter was 13.5 cm. A punch biopsy of a thoracic skin nodule demonstrated a dermal perivascular and periadnexal infiltrate with mild interstitial fibrosis (Image 1B, HE, 203) composed by glycophorin C1 erythroblasts (Image 1C, 603) immature MPO1 granulopoietic elements (Image 1D, 403), and dysmorphic LAT1 megakaryocytes (Image 1E, 603), without CD341 or CD1171 blasts. A diagnosis of postpolycythemia vera myelofibrosis was established on the concurrent bone marrow biopsy (Image 1F,G) [1] and the trilineage hemopoiesis observed on the cutaneous biopsy was consistent with a neoplastic skin involvement by the disease. Cutaneous involvement has been reported in a few patients with myelofibrosis [2–4] and was associated with progressive disease and very poor prognosis [3]. Our patient was asymptomatic and, apart from development of the skin lesions, had no signs of progressive disease, and we, therefore, did not modify his treatment. After a 15 months follow-up, his clinical and hematological picture is stable and the skin lesions show no modifications in size or number. This suggests that cutaneous involvement by myelofibrosis should not be always regarded as a manifestation of the terminal phase of the disease. The observation in adult patients of extramedullary trilineage hemopoiesis, even in absence of blasts, should always rise the suspect of a neoplastic proliferation, which is usually expression of a underlying myeloid proliferation, especially chronic myeloproliferative diseases [5]: thus, as in our case, it is important to integrate the extramedullary findings with clinical picture and results of bone marrow biopsy.

Independent prognostic impact of tumour-infiltrating macrophages in early-stage Hodgkin's lymphoma.

Although patients with early‐stage Hodgkins lymphoma have a high rate of cure, a portion of these are resistant to or relapse after standard treatment. Current prognostic criteria based on clinical and laboratory parameters at diagnosis do not allow to accurately identify the subset of patients with less favourable clinical outcome. An increased number of tumour‐infiltrating macrophages was found to be associated with shortened survival in patients with classic Hodgkins Lymphoma. The aim of this study was to assess the clinical significance of the proportion of CD68‐positive infiltrating macrophages in patients with early‐stage classic Hodgkins lymphoma. By using immunohistochemistry technique, we evaluated for CD68 expression diagnostic biopsies of 106 patients affected by supradiaphragmatic early‐stage classic Hodgkins lymphoma treated at our institution since 2000 to 2010. All patients were treated with adriamycin, bleomycin, vinblastine, and dacarbazine chemotherapy followed by radiotherapy in the majority. The 2‐year overall survival and progression‐free survival (PFS) in the entire cohort were 97% and 83% respectively. The 2‐year PFS was statistically different between patients with favourable and those with unfavourable prognosis according to the European Organisation for Research and Treatment of Cancer (EORTC) risk criteria (96% vs 79%, p = 0.039) and between patients having less than 25% of CD68‐positive infiltrating macrophages and those with more than 25% (85% vs 67%, p = 0.012). All patients with favourable EORTC criteria had CD68 expression lower than 25%. Within those with unfavourable EORTC criteria, patients with a CD68+ count greater than 25% had a worse 2‐year PFS than patients having values lower than 25% (64% vs 82%, p = 0.03). Moreover, in multivariate analysis, after adjusting for CD68+ macrophages count and EORTC score, only CD68+ macrophages count higher than 25% retained a prognostic effect on PFS (hazard ratio = 2.8, 95%CI: 1.1–7.6, p = 0.038). Our data show that a proportion of tumour‐infiltrating macrophages greater than 25% is associated with unfavourable clinical outcome in patients with early‐stage Hodgkins lymphoma Copyright

Effectiveness of photodynamic therapy in refractory plaque‐stage mycosis fungoides associated with Bowen's disease

Dear Editor, Bowen’s disease (BD) is a form of squamous cell carcinoma in situ that can develop into invasive carcinoma if not treated, clinically characterized by an erythematous and scaly plaque that can occur both on sunexposed and non-exposed areas of the skin (Idriss, Misri, & B€ oer-Auer, 2016). Mycosis fungoides (MF) is the most common type of cutaneous T-cell lymphoma (CTCL), and it is characterized by erythematous patches distributed in not-sun exposed areas, which can evolve to

Hemorrhagic vesiculobullous eruption on the palms and the soles as presentation of dyshidrosiform bullous pemphigoid

BP: bullous pemphigoid DP: dyshidrosiform pemphigoid INTRODUCTION Dyshidrosiform bullous pemphigoid (DP) is an unusual localized variant of bullous pemphigoid (BP), first described by Levine et al in 1979. It presents with a persistent and recurrent vesicobullous eruption, sometimes hemorrhagic, localized to the soles and/or palms. Since the clinical manifestations of DP are similar to those of pompholyx or bullous tinea pedis, which are more common and benign dermatologic diseases, a proper diagnosis could be delayed. We report the case of an 82-yearold man affected by DP who was treated for months for pompholyx and bullous tinea pedis with dermatophytid reaction.