Histopathological study of perilesional skin in patients diagnosed with nonmelanoma skin cancer.

BACKGROUND: Epidemiological and clinical data suggest that actinic damage to the skin is an important predictor of skin carcinogenesis. AIM: To investigate the association of squamous cell carcinoma (SCC) and basal cell carcinoma (BCC) with sun-damage alterations seen by histopathology. METHOD: In the current prospective study, perilesional skin of SCC or BCC lesions was evaluated for presence of alterations associated with chronic photodamage. Presence of scarring, perineural/perivascular invasion, haemorrhage/haemorrhagic crust, ulceration/erosion and margin involvement were also assessed. RESULT: Of 6038 included lesions, 4523 (74.9%) were BCCs and 1515 (25.1%) were SCCs. Presence of actinic damage was five times more frequent in SCC than in BCC (OR = 5.29, 95% CI 4.44-6.00, P < 0.001), and diagnosis of SCC was twice as common in photo-exposed than nonphoto-exposed body sites (OR = 2.34, 95% CI 2.03-2.70, P < 0.001). There were twofold higher odds for actinic damage in SCC compared with Bowen disease (OR = 2.015, 95% CI 1.55-2.61, P < 0.001). Assessing the different BCC histological subtypes, we found that nodular BCC had at least twofold higher odds (OR = 2.63, 95% CI 2.09-3.32), infiltrative BCC had 48% higher odds (OR = 1.487, 95% CI 1.18-1.87) and basosquamous BCC had fourfold higher odds (OR = 4.10, 95% CI 3.01-5.57) of having actinic damage compared with superficial BCC. CONCLUSIONS: Histological verification of ultraviolet-associated alterations in the perilesional skin in patients with NMSC in our study confirms the aetiopathogenic link between sun exposure and epithelial carcinogenesis on a histopathological basis. This correlation was stronger for SCCs than for BCCs.

Rosettes and other white shiny structures in polarized dermoscopy: histological correlate and optical explanation.

BACKGROUND: Rosettes are a specific form of a white shiny structure seen with polarized dermoscopy. The precise morphological correlate and optical explication are not known. OBJECTIVE: To estimate the frequency of rosettes in ex vivo dermoscopy and to find explication and morphologic correlate of this dermoscopic feature. METHODS: A series of 6108 consecutive skin biopsies were examined with ex vivo dermoscopy and when rosettes were present serial transverse sections with polarization were examined. RESULTS: In this series of 6108 consecutive skin biopsies, rosettes were found on ex vivo dermoscopy in 63 cases. When multiple we observed that they are always oriented at the same angle. Transverse sections with polarization of these lesions proved that smaller rosettes are mainly caused by polarizing horny material in adnexal openings, and larger rosettes by concentric perifollicular fibrosis. CONCLUSIONS: Rosettes are an optical effect of crossed polarization by concentric fibrosis or horny material and hence are not lesion-specific.

Matter of margins.

BACKGROUND: Basal cell carcinoma (BCC) is the most common cancer, it represents a significant economic burden to health services because of a large volume of affected patients. Surgical excision with histological assessment of the surgical margins is widely considered as the mainstay of BCC treatment. Incomplete removal, in fact, should be considered a poor prognostic indicator, as incomplete removal of lesions is at risk of local recurrence. Actually, dermatological surgeries are carried out by a variety of different types of practitioners, such as plastic surgeons, maxillofacial surgeons, otorhinolaryngologists, ophthalmologists and finally dermatologists. Incomplete removal of the tumour ranges from 6.3% to 25%, depending on the improper intra-operative evaluation of the extent of the tumour. It depends on the clinical knowledge derived from both training and daily experience. In this sense, the majority of the largest studies derive from plastic surgeons, while dermatologists have small case series, albeit with a higher therapeutic efficacy in terms of complete surgical excision. OBJECTIVES: We conducted a retrospective analysis of the surgical activity, more specifically we evaluated both our therapeutic accuracy and analyzed the prognostic factors related to incomplete excisions. METHODS: A retrospective review of all BCC removals was performed. A total of 4523 BCC removals were included; other neoplasm, benign lesions and biopsies were also excluded. Each BCC's size diameter, localization, histology and histological presence of complicating factors was assessed, then the percentage of the incomplete removal was calculated. RESULTS: Incomplete resections occurred in 225 (4.97%) BCCs of the cases. Thirteen areas were categorized into in three different levels that rank the risk of incomplete removals. Sub-analysis indicates that just over a third had no complicating factors with the lateral/deep margins. The most frequent complicating factor is ulceration (22.9%), while vascular invasion or seborrheic keratoses were not found. Actinic keratoses, scabs and scars held the most responsibility for the involvement of the lateral margins, while perineural invasion is the main factor leading to deep margin involvement. Finally, a different trend for the involvement of lateral or deep margins according different histological sub-types was highlighted; lateral involvement is more frequent for the infiltrative/morpheic type, while the deep margin is more involved in the nodular type.

Performance of Enhanced Liver Fibrosis test and comparison with transient elastography in the identification of liver fibrosis in patients with chronic hepatitis B infection.

Assessment of liver fibrosis is important in determining prognosis, disease progression and need for treatment in patients with chronic hepatitis B (CHB). Limitations to the use of liver biopsy in assessing fibrosis are well recognized, and noninvasive tests are being increasingly evaluated including transient elastography (TE) and serum markers such as the Enhanced Liver Fibrosis (ELF) test. We assessed performance of ELF and TE in detecting liver fibrosis with reference to liver histology in a cohort of patients with CHB (n = 182), and compared the performance of these modalities. Median age was 46 and mean AST 70 IU/L. Cirrhosis was reported in 20% of liver biopsies. Both modalities performed well in assessing fibrosis at all stages. Area under receiver operator characteristic (AUROC) curves for detecting METAVIR fibrosis stages F ≥ 1, F ≥ 2, F ≥ 3 and F4 were 0.77, 0.82, 0.80 and 0.83 for ELF and 0.86, 0.86, 0.90 and 0.95 for TE. TE performed significantly better in the assessment of severe fibrosis (AUROC 0.80 for ELF and 0.90 for TE, P < 0.01) and cirrhosis (0.83 for ELF and 0.95 for TE, P < 0.01). This study demonstrates that ELF has good performance in detection of liver fibrosis in patients with CHB, and when compared, TE performs better in detection of severe fibrosis/cirrhosis.

IgG4: not only for allergists.

We describe herein a case of IgG4-related disease with the isolated clinical presentation of malabsorption due to pancreatic failure. Histology of an abdominal lymph node was critical for diagnosis. IgG4-related disease is increasingly recognized as an immunological disorder that can mimic various clinical entities.

Clinical and molecular characterization of diffuse large B-cell lymphomas with 13q14.3 deletion.

BACKGROUND: Deletions at 13q14.3 are common in chronic lymphocytic leukemia and are also present in diffuse large B-cell lymphomas (DLBCL) but never in immunodeficiency-related DLBCL. To characterize DLBCL with 13q14.3 deletions, we combined genome-wide DNA profiling, gene expression and clinical data in a large DLBCL series treated with rituximab, cyclophosphamide, doxorubicine, vincristine and prednisone repeated every 21 days (R-CHOP21). PATIENTS AND METHODS: Affymetrix GeneChip Human Mapping 250K NspI and U133 plus 2.0 gene were used. MicroRNA (miRNA) expression was studied were by real-time PCR. Median follow-up of patients was 4.9 years. RESULTS: Deletions at 13q14.3, comprising DLEU2/MIR15A/MIR16, occurred in 22/166 (13%) cases. The deletion was wider, including also RB1, in 19/22 cases. Samples with del(13q14.3) had concomitant specific aberrations. No reduced MIR15A/MIR16 expression was observed, but 172 transcripts were significantly differential expressed. Among the deregulated genes, there were RB1 and FAS, both commonly deleted at genomic level. No differences in outcome were observed in patients treated with R-CHOP21. CONCLUSIONS: Cases with 13q14.3 deletions appear as group of DLBCL characterized by common genetic and biologic features. Deletions at 13q14.3 might contribute to DLBCL pathogenesis by two mechanisms: deregulating the cell cycle control mainly due RB1 loss and contributing to immune escape, due to FAS down-regulation.

Diagnostic and prognostic impact of serum HE4 detection in endometrial carcinoma patients.

BACKGROUND: To date, no good marker for screening or disease monitoring of endometrial cancer (EC) is available. The aims of this study were to investigate HE4 gene, protein expression and serum HE4 (sHE4) levels in a panel of ECs and normal endometria (NEs) and to correlate sHE4 with patient clinicopathological characteristics and prognosis. METHODS: Using quantitative real-time PCR we tested 46 ECs and 20 NEs for HE4 gene expression. Protein expression was analysed by immunohistochemistry on tissue microarrays in 153 ECs and 33 NEs. Pre-operative serum samples from 138 EC and 76 NE patients were analysed with HE4-EIA assay. Association between sHE4 and patient clinicopathological characteristics or outcome was evaluated. RESULTS: Protein and HE4 gene were significantly upregulated in EC tissues and sera, compared with controls. High sHE4 levels were significantly associated with worse EC clinical characteristics. By univariate survival analysis, high sHE4 levels significantly correlated with decreased overall survival, progression-free survival and disease-free survival, retaining their independent prognostic value on the poorly differentiated EC cohort. CONCLUSION: We demonstrate, for the first time, that high sHE4 levels correlates with an aggressive EC phenotype and may constitute an independent prognostic factor for poorly differentiated-ECs. Determination of sHE4 could be clinically useful in identifying high-risk EC patients for a more aggressive adjuvant therapy.

Plasmacytoid monocytes migrate to inflamed lymph nodes and produce large amounts of type I interferon.

We have identified two cell subsets in human blood based on the lack of lineage markers (lin-) and the differential expression of immunoglobulin-like transcript receptor 1 (ILT1) and ILT3. One subset (lin-/ILT3+/ILT1+) is related to myeloid dendritic cells. The other subset (lin-/ILT3+/ILT1+) corresponds to 'plasmacytoid monocytes'. These cells are found in inflamed lymph nodes in and around the high endothelial venules. They express CD62L and CXCR3, and produce extremely large amounts of type I interferon after stimulation with influenza virus or CD40L. These results, with the distinct cell phenotype, indicate that plasmacytoid monocytes represent a specialized cell lineage that enters inflamed lymph nodes at high endothelial venules, where it produces type I interferon. Plasmacytoid monocytes may protect other cells from viral infections and promote survival of antigen-activated T cells.

BDCA-2, a novel plasmacytoid dendritic cell-specific type II C-type lectin, mediates antigen capture and is a potent inhibitor of interferon alpha/beta induction.

Plasmacytoid dendritic cells are present in lymphoid and nonlymphoid tissue and contribute substantially to both innate and adaptive immunity. Recently, we have described several monoclonal antibodies that recognize a plasmacytoid dendritic cell-specific antigen, which we have termed BDCA-2. Molecular cloning of BDCA-2 revealed that BDCA-2 is a novel type II C-type lectin, which shows 50.7% sequence identity at the amino acid level to its putative murine ortholog, the murine dendritic cell-associated C-type lectin 2. Anti-BDCA-2 monoclonal antibodies are rapidly internalized and efficiently presented to T cells, indicating that BDCA-2 could play a role in ligand internalization and presentation. Furthermore, ligation of BDCA-2 potently suppresses induction of interferon alpha/beta production in plasmacytoid dendritic cells, presumably by a mechanism dependent on calcium mobilization and protein-tyrosine phosphorylation by src-family protein-tyrosine kinases. Inasmuch as production of interferon alpha/beta by plasmacytoid dendritic cells is considered to be a major pathophysiological factor in systemic lupus erythematosus, triggering of BDCA-2 should be evaluated as therapeutic strategy for blocking production of interferon alpha/beta in systemic lupus erythematosus patients.

Identification of CXCL13 as a new marker for follicular dendritic cell sarcoma.

The homeostatic chemokine CXCL13 is preferentially produced in B-follicles and is crucial in the lymphoid organ development by attracting B-lymphocytes that express its selective receptor CXCR5. Follicular dendritic cells (FDCs) have been identified as the main cellular source of this chemokine in lymphoid organs. Recently, genome-wide approaches have suggested follicular CD4 T-helper cells (T(H)F) as additional CXCL13 producers in the germinal centre and the neoplastic counterpart of T(H)F (CD4+ tumour T-cells in angioimmunoblastic T-cell lymphoma) retains the capability of producing this chemokine. In contrast, no data are available on CXCL13 expression on FDC sarcoma (FDC-S) cells. By using multiple approaches, we investigated the expression of CXCL13 at mRNA and protein level in reactive and neoplastic FDCs. In reactive lymph nodes and tonsils, CXCL13 protein is mainly expressed by a subset of FDCs in B-cell follicles. CXCL13 is maintained during FDC transformation, since both dysplastic FDCs from 13 cases of Castleman's disease and neoplastic FDCs from ten cases of FDC-S strongly and diffusely express this chemokine. This observation was confirmed at mRNA level by using RT-PCR and in situ hybridization. Of note, no CXCL13 reactivity was observed in a cohort of epithelial and mesenchymal neoplasms potentially mimicking FDC-S. FDC-S are commonly associated with a dense intratumoural inflammatory infiltrate and immunohistochemistry showed that these lymphocytes express the CXCL13 receptor CXCR5 and are mainly of mantle zone B-cell derivation (IgD+ and TCL1+). In conclusion, this study demonstrates that CXCL13 is produced by dysplastic and neoplastic FDCs and can be instrumental in recruiting intratumoural CXCR5+ lymphocytes. In addition to the potential biological relevance of this expression, the use of reagents directed against CXCL13 can be useful to properly identify the origin of spindle cell and epithelioid neoplasms.

A practical algorithmic approach to mature aggressive B cell lymphoma diagnosis in the double/triple hit era: selecting cases, matching clinical benefit : A position paper from the Italian Group of Haematopathology (G.I.E.).

An accurate diagnosis of clinically distinct subgroups of aggressive mature B cell lymphomas is crucial for the choice of proper treatment. Presently, precise recognition of these disorders relies on the combination of morphological, immunophenotypical, and cytogenetic/molecular features. The diagnostic workup in such situations implies the application of costly and time-consuming analyses, which are not always required, since an intensified treatment option is reasonably reserved to fit patients. The Italian Group of Haematopathology proposes herein a practical algorithm for the diagnosis of aggressive mature B cell lymphomas based on a stepwise approach, aimed to select cases deserving molecular analysis, in order to optimize time and resources still assuring the optimal management for any patient.

Correction to: A practical algorithmic approach to mature aggressive B cell lymphoma diagnosis in the double/triple hit era: selecting cases, matching clinical benefit.

The first and family names of the authors were interchanged and are now presented correctly. The original article has been corrected.

Late computed tomography scan response improvement and gallium scintigraphy evaluation as on-treatment prognostic parameters to tailor treatment intensity in patients with Hodgkin's lymphoma. A prospective phase II study.

BACKGROUND: Tailoring treatment intensity is critical in Hodgkin's lymphoma (HL). Ongoing prognostic parameters may be an useful adjunct to pretreatment stratification. We used the kinetics of computed tomography (CT) scan response and residual gallium (Ga)-67 uptake to better stratify risk. MATERIALS AND METHODS: Patients received 4-8 adriamycin, bleomycin, vinblastine and dacarbazine courses according to stage. Disease was reassessed evaluating late computed tomography scan response improvement (CTRI) and Ga-67 uptake. Patients received no further treatment, radiotherapy (RT) or additional chemotherapy + RT according to the presence of none (low risk), one (intermediate risk) and both parameters (high risk). Patients with bulky mediastinum received RT anyhow. RESULTS: Among 102 assessable patients, 35 showed late CTRI and 9 residual Ga-67 uptake. In 30 patients with bulky mediastinum, the 3-year progression-free survival (PFS) was significantly better when neither parameter was present (100% versus 69%; P = 0.02). In 72 patients without bulky mediastinum, treatment was tailored according to risk assignment. Relapses occurred in 5 of 47 low-risk and 3 of 21 intermediate-risk patients, with no differences between the two groups, and in 3 of 4 high-risk patients. CONCLUSION: This study shows that two on-treatment parameters, late CTRI and residual Ga-67 uptake, can predict PFS in HL and identify patients in which RT can be spared without apparently affecting the outcome.

Failure of adefovir 20 mg to improve suboptimal response in lamivudine-resistant hepatitis B patients treated with adefovir 10 mg and lamivudine.

Nine patients with lamivudine-resistant chronic hepatitis B infection who had been treated with adefovir 10 mg/day and had had a suboptimal response but did not have genotypic resistance to adefovir were treated with high-dose adefovir (20 mg/day). The response to the increased dose of adefovir was compared with the response in 15 patients with a suboptimal response who did not receive an increase in the dose of adefovir. The increase in the dose of adefovir did not lead to a significant reduction in hepatitis B DNA when compared with patients maintained on the standard dose. These data suggest that increasing the dose of adefovir in patients with a suboptimal response does not lead to an improved response.

Claudin-7 expression in human epithelial ovarian cancer.

Claudin-7 (CLDN-7) is a tight junction protein recently found highly differentially expressed in ovarian carcinoma. To evaluate its potential as a novel biomarker, in this study, we quantified and compared claudin-7 expression at messenger RNA and protein level in 110 patients harboring various histologic types of epithelial ovarian carcinomas (EOC). CLDN-7 transcript was found significantly overexpressed in both primary and metastatic EOCs compared to normal human ovarian surface epithelium cell lines (fold change = 111.4, P < 0.001) by reverse transcription-polymerase chain reaction. At the protein level, CLDN-7 expression was found significantly higher in tumors of primary and metastatic origin when compared to normal ovaries (P < 0.001), regardless of the histologic type, the grade of differentiation, and the pathologic stage of the disease (P = 0.12). Moreover, a strong immunoreactivity for CLDN-7 was detected in EOC cells present in ascites fluids, whereas ascites-derived inflammatory cells, histiocytes, and reactive mesothelial cells were negative. Finally, immunohistochemical expression of CLDN-7 was observed in several human normal epithelial control tissues analyzed. CLDN-7 is significantly overexpressed in all main histologic types of EOC and in single neoplastic cells disseminated in peritoneal cavity and pleural effusions, suggesting its potential role as novel diagnostic marker in ovarian cancer. Despite widespread expression of CLDN-7 in several human normal tissues, the high density of CLDN-7 molecules, their membranous localization on EOC cells, and their lack of expression on the celomic epithelium in the peritoneal cavity suggest that this target could be potentially suitable for antibody-mediated localized therapies of ovarian adenocarcinoma.

Clinical features and outcomes of hepatocellular carcinoma in Caucasian cirrhotic patients on long-term analogue therapy for hepatitis B.

BACKGROUND: Long-term oral nucleos(t)ide analogue (NUC) therapy in hepatitis B virus (HBV)-related compensated cirrhotics prevents clinical decompensation but not hepatocellular carcinoma (HCC) development. AIMS: To define the clinical features and outcomes of HCC in long-term NUC-treated HBV patients. METHODS: All HCCs developing between 2005 and 2016 in NUC-treated HBV patients under surveillance were studied, excluding those that occurred within the first 6 months of therapy. Clinical features of HCC, alpha faetoprotein (AFP) patterns and patients' outcome were studied. RESULTS: Seventy-six HCC patients were included. Median age was 67 (40-83) years, 84% males, 96% Caucasian, 95% HBeAg-negative, 96% with undetectable HBV DNA, 83% with normal ALT levels, and 92% with compensated cirrhosis. Median serum AFP levels were 4 (1-3615) ng/mL (>7 ng/mL in 36%). HCC was monofocal in 78%, had a median diameter of 20 (6-57) mm and was in its early stage in 92% which allowed potentially curative treatments in 78% (39% ablation, 28% surgical resection, 11% liver transplantation). Overall, a complete response was obtained in 61 (80%) patients: in 40 after a first-line treatment, in 3 after the second-line treatment, in 2 after the third-line treatment, while 16 underwent liver transplantation (8 as second line). During 45 (7-144) months after HCC diagnosis, 19 patients died, 84% from HCC progression. The median time to recurrence was 20.2 (3-53) months, and the cumulative 5-year liver-related survival was 74%. CONCLUSIONS: HCCs developing in patients under long-term NUC treatment were single, small tumours, amenable to curative therapies able to confer excellent 5-year survival rates.

Studies of the expression of the Wiskott-Aldrich syndrome protein.

The Wiskott-Aldrich syndrome (WAS) is an X-linked disorder characterized by thrombocytopenia, eczema, disorders in cell-mediated and humoral immunity, and a proclivity to lymphoproliferative disease. The gene responsible encodes a 53-kD proline-rich protein of unknown function (WASP). We produced a FLAG-WASP fusion protein that was used to immunize mice and produce mAbs against WASP. Using monoclonal anti-WASP in Western immunoblots, we have determined that WASP is present in the cytoplasmic but not nuclear fraction of normal human peripheral blood mononuclear cells, in normal human platelets, in T lymphocytes, non-T lymphocytes, and monocytes. The protein is produced in the B cell immunoblastic cell line DS-1, in normal EBV-transformed B cell lines, and in HEL92.1.7, but is barely detectable in MOLT-4 and not detectable in K562. WASP was present in two of four EBV-transformed cell lines from WAS patients. Splenic tissue immunostaining was performed in two patients, and the results correlated with the results of the Western blots. Sequence analysis of WASP cDNA from two patients who produce WASP show mutations causing amino acid substitutions. These studies establish a foundation for further studies aimed at understanding the function of WASP.

Cancer stem cells and therapeutic perspectives.

The cancer stem cell hypothesis suggests that neoplastic clones are maintained exclusively by a rare fraction of cells with stem cell proprieties. Stem cells are defined as cells which are able to both extensively self-renew and differentiate into progenitors. Furthermore, stem cells are also attractive candidates as origin of cancers, as in their long lifespan mutations and epigenetic changes they can increase allowing for increasing evolution toward malignancy. Herein, we discuss the evidences reported in literature on existence of cancer stem cells in several tumors and mechanisms of the extrinsic and intrinsic circuitry controlling stem cell fate as well as their possible connections to cancer. In particular, the review will focus on recent results on conserved Polycomb Group (PcG) gene family, an epigenetic chromatin modifiers involved in cancer development and also in the maintenance of embryonic and adult stem cells. There are two distinct multiprotein PcG complexes identified, Polycomb repressive complex (PRC) 1 and 2. The fact that either PRC1 Bmi1 than PRC2 SU(Z)12 components are implicated in self-renewal stem cells and up-regulated in several kind of human cancer, confirm the importance of (de)regulation of the PcG genes in cancer and stem cell biology. Moreover, Bmi1 and SU(Z)12 are downstream target of Sonic hedgehog (Shh) and Wnt signaling respectively, providing for a connection between epigenetic change regulators (PcG) and developmental-signaling pathways. Finally, potential therapies using inhibitors acting on cancer stem cell population such as cyclopamine, an inhibitor of hedgehog signalling, 6-bromoindirubin-3'-oxime (BIO) which acts on GSK3 and inhibitors of beta-catenin signaling such as exisulind and the tyrosine-kinase inhibitor STI571/Gleevac/imatinib will also discuss.