Detection of the Merkel cell polyomavirus in the neuroendocrine component of combined Merkel cell carcinoma

Abstract

Merkel cell carcinoma (MCC) is an aggressive neuroendocrine carcinoma of the skin. The main etiological agent is Merkel cell polyomavirus (MCPyV), detected in 80% of cases. About 5% of cases, called combined MCC, feature an admixture of neuroendocrine and non-neuroendocrine tumor cells. Reports of the presence or absence of MCPyV in combined MCC are conflicting, most favoring the absence, which suggests that combined MCC might have independent etiological factors and pathogenesis. These discrepancies might occur with the use of different virus identification assays, with different sensitivities. In this study, we aimed to determine the viral status of combined MCC by a multimodal approach. We histologically reviewed 128 cases of MCC and sub-classified them as "combined" or "conventional." Both groups were compared by clinical data (age, sex, site, American Joint Committee on Cancer [AJCC] stage, immunosuppression, risk of recurrence, and death during follow-up) and immunochemical features (cytokeratin 20 and 7, thyroid transcription factor 1 [TTF1], p53, large T antigen [CM2B4], CD8 infiltrates). After a first calibration step with 12 conventional MCCs and 12 cutaneous squamous cell carcinomas as controls, all eight cases of combined MCC were investigated for MCPyV viral status by combining two independent molecular procedures. Furthermore, on multiplex genotyping assay, the samples were examined for the presence of other polyoma- and papillomaviruses. Combined MCC differed from conventional MCC in earlier AJCC stage, increased risk of recurrence and death, decreased CD8 infiltrates, more frequent TTF1 positivity (5/8), abnormal p53 expression (8/8), and frequent lack of large T antigen expression (7/8). With the molecular procedure, half of the combined MCC cases were positive for MCPyV in the neuroendocrine component. Beta papillomaviruses were detected in 5/8 combined MCC cases and 9/12 conventional MCC cases. In conclusion, the detection of MCPyV DNA in half of the combined MCC cases suggests similar routes of carcinogenesis for combined and conventional MCC.

https://ift.tt/2E0R8C4

Immune cell expression of TGFβ1 in cancer with lymphoid stroma: dendritic cell and regulatory T cell contact

Abstract

Although cancer tissue generally shows limited immune responses, some cancers abound with lymphocytes, which generally show favorable prognosis. These cancers, despite their rarity, are important in analyzing immune responses in cancer tissue. Transforming growth factor β1 (TFGβ1) is a multifunctional cytokine, generally having an immunosuppressive function. The present study analyzes the in situ TGFβ1 expression in 23 cases of lymphocyte-rich gastric carcinomas (Ly-rich GCs) using immunohistochemistry and in situ hybridization. Immunohistochemistry revealed that latency-associated peptide (LAP) of TGFβ1 was localized in mainly immune cells in all cases, which was more abundant than in control GCs. Expression of LAP by cancer cells was only focal. In situ hybridization also confirmed abundant TGFβ1 mRNA expression in the lymphoid stroma. Double immunofluorescent microscopy identified LAP⁺ cells as macrophages, dendritic cells, and part of T cells. Close cell-to-cell contact was observed between LAP⁺ dendritic-shaped cells and FoxP3⁺ regulatory T cells (T_reg cells). Mature dendritic cells in Ly-rich GCs expressed LAP more frequently than those in the secondary lymphoid organs. Our data revealed abundant expression of TGFβ1 in immune cells with contact to T_reg cells in lymphoid stroma, which is consistent with the notion that TGFβ1 is one of the immunosuppressive factors in cancer stroma.

https://ift.tt/2Ge9tBY

Analysis of membranous Ki-67 staining in breast cancer and surrounding breast epithelium

Abstract

Membranous Ki-67 staining with the MIB-1 antibody has been described in hyalinising trabecular adenomas of the thyroid and sclerosing haemangiomas of the lung. Its relatively rare occurrence in breast tumours has also been documented. The aim of the present study was to assess the rate of any membranous MIB-1 staining in breast specimens. The staining was performed at room temperature with 1:100 dilution of the antibody. One hundred four core needle biopsies and 41 operative specimens were analysed. Membranous staining was noted in 36/144 invasive carcinomas, 20/42 in situ carcinomas and 46/99 cases of peritumoural benign/normal breast epithelium. Most often, it presented as focal and partial polarised luminal membranous staining although complete circumferential staining also occurred, and membranous labelling was sometimes accompanied by cytoplasmic staining, too. In a few cases tested, greater dilution of the primary antibody did not abolish the membranous staining, which was absent with the SP6 monoclonal Ki-67 antibody. The membranous staining of invasive tumours showed no association with histological grade, lumen formation, oestrogen or progesterone receptor status or the Ki-67 nuclear labelling. In contrast, it was associated with a HER2-positive status, although it occurred in all molecular subtypes approached by immunohistochemistry. The background of this membranous staining remains elusive. It is unlikely to represent an artefact. At least partial sharing of an epitope of the nuclear Ki-67 protein with an unidentified membranous protein and some functional differences between membranous staining producing tumours and tumours lacking this pattern of staining may both contribute to some extent.

https://ift.tt/2E0R9G8

Blockade of TNFR1-dependent and -independent cell death is crucial for normal epidermal differentiation

Publication date: Available online 27 March 2018
Source:Journal of Allergy and Clinical Immunology
Author(s): Xuehua Piao, Ryosuke Miura, Sanae Miyake, Sachiko Komazawa-Sakon, Masato Koike, Ryodai Shindo, Junji Takeda, Akito Hasegawa, Riichiro Abe, Chiharu Nishiyama, Tetsuo Mikami, Hideo Yagita, Yasuo Uchiyama, Hiroyasu Nakano
BackgroundDelicate balance between cell death and proliferation of keratinocytes is crucial for normal development of the skin. Previous studies have reported that cellular FLICE-inhibitory protein (cFLIP) plays a crucial role in prevention of keratinocytes from TNFα-dependent apoptosis and blocking the development of dermatitis. However, a role for cFLIP in TNFα-independent cell death remains unclear.ObjectiveWe investigated contribution of TNFα-dependent and -independent signals to the development of dermatitis in epidermis-specific Cflar-deficient (Cflar^E-KO) mice.MethodsWe examined histology, and expression of epidermal differentiation markers and inflammatory cytokines of the skin of Cflar^E-KO ;Tnfrsf1a+/- and Cflar^E-KO ;Tnfrsf1a-/- mice. To block TNFα-independent cell death of Cflar^E-KO;Tnfrsf1a-/- mice, mice were treated with neutralizing antibodies against FasL and TRAIL.ResultsCflar^E-KO;Tnfrsf1a-/- mice were born, but developed severe dermatitis and succumbed soon after birth. Cflar^E-KO;Tnfrsf1a+/- mice exhibited embryonic lethality due to massive apoptosis of keratinocytes. While keratinocytes from Cflar^E-KO;Tnfrsf1a-/- mice still died by apoptosis, neutralizing antibodies against FasL and TRAIL substantially prolonged survival of Cflar^E-KO;Tnfrsf1a-/- mice. Expression of inflammatory cytokines, such as interleukin (Il)6 and Il17a was elevated, conversely, expression of epidermal differentiation markers was severely downregulated in the skin of Cflar^E-KO;Tnfrsf1a-/- mice. Treatment of primary keratinocytes with IL-6, and to a lesser extent IL-17A suppressed expression of epidermal differentiation markers.ConclusionTNFR1-dependent or -independent apoptosis of keratinocytes promotes inflammatory cytokine production that subsequently blocks epidermal differentiation. Thus, blockade of both TNFR1-dependent and -independent cell death might be an alternative strategy to treat skin diseases when treatment with anti-TNFα antibody alone is not sufficient.

Teaser

Epidermis-specific deletion of Cflar gene uncovers that prevention of both TNFR1-dependent and -independent apoptosis is crucial for the maintenance of normal epidermal differentiation.


https://ift.tt/2E0wzpL

Immune Checkpoint Blockade Therapy

Publication date: Available online 27 March 2018
Source:Journal of Allergy and Clinical Immunology
Author(s): Thomas Wieder, Thomas Eigentler, Ellen Brenner, Dipl Biol, Martin Röcken
Immune checkpoints are accessory molecules that either promote or inhibit T cell activation. Two inhibitory molecules, cytotoxic T cell antigen 4 (CTLA-4) and programmed death 1 (PD-1), got high attention, as inhibition of CTLA-4 or PD-1 signaling provides the first immune therapy that significantly improves the survival of patients with metastatic solid cancers. Inhibition of CTLA-4 or PD-1 was first studied in and approved for patients with metastatic melanoma. Blocking immune checkpoints is also efficient in non-small-cell lung cancer, renal cell cancers, hypermutated gastro-intestinal cancers and others. Immune responses, whether directed against infections or against tumors, are divided into two phases: an initiation and activation phase, where the immune system recognizes a danger signal and becomes activated by innate signals to fight the danger. This reaction is fundamental for the control of infections and cancer, but needs to be turned off once the danger is controlled, as persistence of this activation ultimately causes severe tissue damage. Therefore, each activation of the immune system is followed by a termination phase, where endogenous immune suppressor molecules arrest immune responses to prevent harmful damage. In the case of cancer immune therapies, therapeutic approaches classically enhanced the initiation and activation of immune responses to increase the emergence and the efficacy of cytotoxic T cells (CTL) against cancers. In sharp contrast, immune checkpoint blockade focuses on the termination of immune responses by inhibiting immune suppressor molecules. It thus prevents the termination of immune responses or even awakes those CTLs that became exhausted during an immune response. Therefore, blocking negatively regulating immune checkpoints restores the capacity of exhausted CTL to kill the cancer they infiltrate. In addition, they drive surviving cancer cells into a still poorly defined state of dormancy. As the therapy awakes also self-reactive CTL, one downside of the therapy is the induction of organ-specific autoimmune diseases. The second downside is the exorbitant drug price that withdraws patients at need from a therapy that was developed by academic research that impairs further academic treatment development and financially charges the public health system.



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Calcifying Odontogenic Cyst Showing a Varied Epithelial Lining: An Additional Case with Implications for the Divergent Differentiation Capacity of the Cyst Epithelium

https://ift.tt/2IVj9Pr

Seromucinous Hamartoma of the Nasal Cavity

Abstract

Seromucinous hamartoma (SMH) is a rare benign epithelial proliferation occurring in the sinonasal tract. The clinical, radiographic, and histologic appearance of SMH may mimic several benign and malignant entities. Presented is a novel case, with a review of the literature focused on potential histologic diagnostic pitfalls.

https://ift.tt/2I9vmi4