Recurrence of Mycosis Fungoides on Multiple Melanocytic Nevi: A Case Report and Review of the Literature

Melanocytic nevi represent a widespread cutaneous finding. Nevertheless, the presence of mycosis fungoides and melanocytic nevi in the same location is an extremely rare event. We report the case of a patient affected by mycosis fungoides and treated with PUVA therapy, with complete remission of the disease. Eight years after therapy discontinuation, he presented epidermal scaling and an erythematous perinevic halo on 3 old melanocytic lesions, the clinical aspect of which was highly suggestive for Meyerson nevi. The histological and immunohistochemical examination of an excised melanocytic lesion revealed histological features consistent with the diagnosis of mycosis fungoides superimposed on junctional melanocytic nevi. The finding of patches of mycosis fungoides superimposed on melanocytic nevi is a rare event; the confounding clinical appearance with eczematous changes around a pre-existing nevus may recall the halo dermatitis known as Meyerson phenomenon; this highlights the importance of clinical and histological examination to make the correct diagnosis of dermatological diseases

a study to discover novel tumor-specific mutations

Background Splenic marginal zone lymphoma (SMZL) is an indolent B-cell non- Hodgkin lymphoma and represents the most common primary malignancy of the spleen. Its precise molecular pathogenesis is still unknown and specific molecular markers for diagnosis or possible targets for causal therapies are lacking. Methods We performed whole exome sequencing (WES) and copy number analysis from laser-microdissected tumor cells of two primary SMZL discovery cases. Selected somatic single nucleotide variants (SNVs) were analyzed using pyrosequencing and Sanger sequencing in an independent validation cohort. Results Overall, 25 nonsynonymous somatic SNVs were identified, including known mutations in the NOTCH2 and MYD88 genes. Twenty-three of the mutations have not been associated with SMZL before. Many of these seem to be subclonal. Screening of 24 additional SMZL for mutations at the same positions found mutated in the WES approach revealed no recurrence of mutations for ZNF608 and PDE10A, whereas the MYD88 L265P missense mutation was identified in 15 % of cases. An analysis of the NOTCH2 PEST domain and the whole coding region of the transcription factor SMYD1 in eight cases identified no additional case with a NOTCH2 mutation, but two additional cases with SMYD1 alterations. Conclusions In this first WES approach from microdissected SMZL tissue we confirmed known mutations and discovered new somatic variants. Recurrence of MYD88 mutations in SMZL was validated, but NOTCH2 PEST domain mutations were relatively rare (10 % of cases). Recurrent mutations in the transcription factor SMYD1 have not been described in SMZL before and warrant further investigation

Whole exome sequencing of microdissected splenic marginal zone lymphoma: a study to discover novel tumor-specific mutations

BACKGROUND: Splenic marginal zone lymphoma (SMZL) is an indolent B-cell non-Hodgkin lymphoma and represents the most common primary malignancy of the spleen. Its precise molecular pathogenesis is still unknown and specific molecular markers for diagnosis or possible targets for causal therapies are lacking. METHODS: We performed whole exome sequencing (WES) and copy number analysis from laser-microdissected tumor cells of two primary SMZL discovery cases. Selected somatic single nucleotide variants (SNVs) were analyzed using pyrosequencing and Sanger sequencing in an independent validation cohort. RESULTS: Overall, 25 nonsynonymous somatic SNVs were identified, including known mutations in the NOTCH2 and MYD88 genes. Twenty-three of the mutations have not been associated with SMZL before. Many of these seem to be subclonal. Screening of 24 additional SMZL for mutations at the same positions found mutated in the WES approach revealed no recurrence of mutations for ZNF608 and PDE10A, whereas the MYD88 L265P missense mutation was identified in 15 % of cases. An analysis of the NOTCH2 PEST domain and the whole coding region of the transcription factor SMYD1 in eight cases identified no additional case with a NOTCH2 mutation, but two additional cases with SMYD1 alterations. CONCLUSIONS: In this first WES approach from microdissected SMZL tissue we confirmed known mutations and discovered new somatic variants. Recurrence of MYD88 mutations in SMZL was validated, but NOTCH2 PEST domain mutations were relatively rare (10 % of cases). Recurrent mutations in the transcription factor SMYD1 have not been described in SMZL before and warrant further investigatio

Genetic and phenotypic attributes of splenic marginal zone lymphoma

Splenic marginal zone B-cell lymphoma (SMZL) is a heterogeneous clinico-biological entity. The clinical course is variable, multiple genes are mutated with no unifying mechanism, and essential regulatory pathways and surrounding microenvironments are diverse. We sought to clarify the heterogeneity of SMZL by resolving different subgroups and their underlying genomic abnormalities, pathway signatures, and microenvironment compositions to uncover biomarkers and therapeutic vulnerabilities. We studied 303 SMZL spleen samples collected through the IELSG46 multicenter international study (NCT02945319) by using a multiplatform approach. We carried out genetic and phenotypic analyses, defined self-organized signatures, validated the findings in independent primary tumor metadata and in genetically modified mouse models, and determined correlations with outcome data. We identified 2 prominent genetic clusters in SMZL, termed NNK (58% of cases, harboring NF-κB, NOTCH, and KLF2 modules) and DMT (32% of cases, with DNA-damage response, MAPK, and TLR modules). Genetic aberrations in multiple genes as well as cytogenetic and immunogenetic features distinguished NNK- from DMT-SMZLs. These genetic clusters not only have distinct underpinning biology, as judged by differences in gene-expression signatures, but also different outcomes, with inferior survival in NNK-SMZLs. Digital cytometry and in situ profiling segregated 2 basic types of SMZL immune microenvironments termed immune-suppressive SMZL (50% of cases, associated with inflammatory cells and immune checkpoint activation) and immune-silent SMZL (50% of cases, associated with an immune-excluded phenotype) with distinct mutational and clinical connotations. In summary, we propose a nosology of SMZL that can implement its classification and also aid in the development of rationally targeted treatments

Genetic Characterization and Clinical Features of Helicobacter pylori Negative Gastric Mucosa-Associated Lymphoid Tissue Lymphoma

Background: In Western countries, the prevalence of gastric mucosa-associated lymphoid tissue (MALT) lymphoma has declined over the last three decades. Contemporaneously, H. pylori negative gastric MALT lymphoma is increasingly encountered, and their genetic basis and clinical features remain elusive. Methods: A total of 57 cases of H. pylori negative gastric MALT lymphoma were reviewed and investigated for chromosome translocation by fluorescence in-situ hybridization and for somatic mutations by the targeted sequencing of 93 genes. Results: MALT1 translocation, most likely t(11;18)(q21;q21)/BIRC3-MALT1, was detected in 39% (22/57) cases, and IGH translocation was further seen in 12 MALT1-negative cases, together accounting for 60% of the cohort. Targeted sequencing was successful in 35 cases, and showed frequent mutations in NF-κB signaling pathways (TNFAIP3 = 23%, CARD11 = 9%, MAP3K14 = 9%), together affecting 14 cases (40%). The NF-κB pathway mutations were mutually exclusive from MALT1, albeit not IGH translocation, altogether occurring in 86% of cases. There was no significant correlation between the genetic changes and clinicopathological parameters. The patients showed a median of progression-free survival (PFS) of 66.3 months, and a significant superior PFS when treated with systemic versus antibiotic therapy (p = 0.004). Conclusion: H. pylori negative gastric MALT lymphoma is characterized by highly frequent genetic changes in the NF-κB signaling pathways

Normal and neoplastic cells of brown adipose tissue express the adhesion molecule CD31.

CONTEXT: CD31 (platelet-endothelial cell adhesion molecule-1; PECAM-1), an adhesion molecule involved in the process of angiogenesis, is used as a marker of normal and neoplastic vascularization. During the assessment of angiogenesis and vascular invasion in a thymic carcinoid tumor, we observed unexpected immunostaining for CD31 in perithymic brown fat nests. OBJECTIVE: To determine whether CD31 is expressed by normal and neoplastic cells of brown fat, a tissue whose thermogenetic activity depends heavily on high perfusion. DESIGN: Formalin-fixed, paraffin-embedded archival tissues were immunostained by the labeled avidin-biotin method using antibodies against CD31 (clones JC70A and 1A10) after retrieval of heat-induced epitopes. Archival tissues included perithymic, periadrenal, axillary, and neck adipose tissue in which were embedded nests of brown fat (n = 15), hibernoma (n = 3), lipoma (n = 6), well-differentiated liposarcoma (n = 4), and myxoid liposarcoma (n = 4). RESULTS: Invariably, multivacuolated and univacuolated adipocytes of normal brown fat and hibernomas were intensely positive for the CD31 antigen. The immunostaining "decorated" cell membranes and the membranes of intracytoplasmic vacuoles. No expression of CD31 was found in normal adipocytes of white fat, in neoplastic cells of lipomas, or in multivacuolated lipoblasts of well-differentiated and myxoid liposarcomas. CONCLUSIONS: The spectrum of cell types that express CD31 is expanded to include normal and neoplastic brown fat cells. We speculate that the expression of CD31 may play a role in the development and maintenance of the vascular network characterizing this specialized adipose tissue. Moreover, CD31 may inhibit the Bax-mediated apoptosis of brown fat cells. For practical purposes, CD31 may be used as an immunohistochemical marker for distinguishing between white and brown fat and for diagnosing hibernoma in paraffin sections

Leukocytoclastic vasculitis as a complication of recombinant granulocyte colony-stimulating factor therapy in a heart transplant patient.

Recombinant granulocyte colony-stimulating factor (rG-CSF) is a myeloid growth factor that is widely used in haematology to recover neutropenia secondary to myelosuppressive chemotherapy. Leukocytoclastic vasculitis is an acknowledged side effect of the above therapy. Its pathogenesis involves many mechanisms that collectively induce an increase in neutrophil function and a subsequent release of cytokines. Here, we report a case of leukocytoclastic vasculitis proven by skin biopsy, following the use of rG-CSF in a heart transplant patient with leukopenia secondary to immunosuppressive therapy

Open partial horizontal laryngectomy for salvage after failure of CO2 laser-assisted surgery for glottic carcinoma.

Total laryngectomy (TL) is often still recommended as a salvage approach for recurrent laryngeal squamous cell carcinoma (LSCC). Considering LSCC recurrences after the failure of primary transoral laser microsurgery (TLM), open partial horizontal laryngectomy (OPHL) could be a valid alternative to TL in selected patients. The aim of the present study was to analyze retrospectively the oncological outcome of a consecutive series of 17 patients treated at the Otolaryngology Unit of Vittorio Veneto Hospital (Italy) with OPHL after primary TLM had failed. Nine patients (53 %) had no further recurrences after salvage OPHL. Eight patients had a second recurrence of LSCC after OPHL, and five of them were cured by further salvage treatment, while the other three died of their disease. We found an overall and diseasespecific survival both of 82 % and a loco-regional control rate and an ultimate organ preservation rate of 82 and 70 %, respectively. Patients who underwent two-stage bilateral cordectomy for primary glottic carcinoma showed a trend towards a higher rate of second recurrences, a lower ultimate organ preservation rate and a shorter disease-free survival after salvage OPHL. Further studies on larger cohorts of patients are needed to identify potential clinical and/or pathological prognostic parameters capable of pinpointing patients at higher risk of second recurrences after salvage OPHL in cases where TLM has failed. A salvage TL might be reasonably proposed as a first salvage choice in such cases