Mycosis fungoides (MF) is the most frequent type of cutaneous T-cell lymphoma, whose diagnosis and study is hampered by its morphologic similarity to inflammatory dermatoses (ID) and the low proportion of tumoral cells, which often account for only 5% to 10% of the total tissue cells. cDNA microarray studies using the CNIO OncoChip of 29 MF and 11 ID cases revealed a signature of 27 genes implicated in the tumorigenesis of MF, including tumor necrosis factor receptor (TNFR)-dependent apoptosis regulators, STAT4, CD40L, and other oncogenes and apoptosis inhibitors. Subsequently a 6-gene prediction model was constructed that is capable of distinguishing MF and ID cases with unprecedented accuracy. This model correctly predicted the class of 97% of cases in a blind test validation using 24 MF patients with low clinical stages. Unsupervised hierarchic clustering has revealed 2 major subclasses of MF, one of which tends to include more aggressive-type MF cases including tumoral MF forms. Furthermore, signatures associated with abnormal immunophenotype (11 genes) and tumor stage disease IntroductionMycosis fungoides (MF) is a peripheral cutaneous T-cell lymphoma (CTCL) characterized by the infiltration and accumulation of tumoral T cells in the skin (epidermal and dermal infiltration). 1 It is the most frequent type of CTCL, representing more than half of all lymphomas originating in the skin. 2 Clinical and pathologic diagnosis of MF has proved very difficult since it bears many resemblances to common inflammatory dermatoses (ID) such as interface and spongiotic dermatitis, conditions involving infiltration and accumulation of benign T cells in the skin. The study of MF is further compounded by the small number of tumoral cells, which may be present in the skin, with tumoral T-cell infiltrate often accounting for only 5% to 10% of the total tissue cells. Most CTCLs have the phenotype of T-helper memory lymphocytes (CD3 ϩ , CD4 ϩ ) with only a minority of cases showing phenotypes such as CD4 Ϫ or CD8 ϩ , with CD8 ϩ cases possibly representing a subset of aggressive cases. 3 Additionally, loss of CD7 expression is considered a distinguishing characteristic of MF. 4 The etiology of MF remains largely unknown, although some triggering factors such as chronic antigen stimulation 5 or human T-cell lymphotropic virus type 1 or other viral infections have been proposed. However, some of these findings have been somewhat contentious. 6,7 Molecular studies of MF have revealed some interesting facts, although the studies are confined to small groups of genes and proteins. Defective FAS signaling has been suggested as a possible causative agent in MF pathogenesis due to defects in apoptosis signaling in skin-homing T cells. 8 Reduction of FAS expression has been documented in peripheral blood CD4 ϩ T lymphocytes in CTCL. 9 This decreased FAS expression may be the result of FAS mutations, which are infrequent but are present in some cases. 8 Defective FAS signaling may also be supplemented by mutations or defects in caspases or ...

The membrane-cytoskeleton crosslinker ezrin is associated with malignant progression and metastasis in human neoplasias. To study the role of ezrin in breast cancer, we first assessed ezrin expression in a panel of breast cancer cell lines by western blot and confocal microscopy. Western blot revealed no differences in total ezrin levels among these breast cell lines. However, immunofluorescence staining revealed that Estrogen receptor (ER)-positive, noninvasive and nontumorigenic cell lines concentrated ezrin at the apical surface, whereas invasive cell lines localized ezrin in motile structures (membrane ruffles and filopodia) but also had more diffuse cytoplasmic staining. We next studied ezrin expression in 509 breast carcinomas using tissue microarrays. Immunohistochemical staining for ezrin, p53, Ki-67, phospho-Akt, HER2, and hormonal receptors was performed. Ezrin staining in normal breast epithelium localized at the apical, but not lateral, cell surface, whereas, in most breast tumor cases (331, 70.3%), it localized in the cytoplasm. Complete membranous staining occurred in 89 (18.9%) samples, and apical staining was seen in 51 (10.8%) cases. There were significant positive associations between cytoplasmic ezrin localization and adverse tumor characteristics such as high grade, high level of Ki-67 expression, hormonal-receptor negativity, and lymph-node metastases. Apical ezrin staining was associated with favorable clinicopathological features and node-negative tumors. Membranous ezrin staining was associated with high grade, strong HER2 and p-Akt expression. In conclusion, the switch of ezrin localization from the apical membrane to either the complete membrane or to the cytoplasm is correlated with dedifferentiation and adverse features in invasive breast tumors and cancer cell lines.

Association of Hodgkin lymphoma and non-Hodgkin lymphoma is rare and, specifically, the combination of Hodgkin lymphoma and mantle cell lymphoma has not been previously described. Here we describe composite mantle cell lymphoma and Hodgkin lymphoma affecting the spleen in one case and the eyelid and cervical lymph nodes in a second. In both, nodules of classical Hodgkin lymphoma were intermixed with diffuse or nodular areas of typical mantle cell lymphoma. Immunohistochemical and molecular analyses confirmed cyclin D1 overexpression secondary to the translocation t(11;14) in the small mantle cell lymphoma component; with CD30, CD15, and EBV expression in the Hodgkin and Reed-Sternberg cells. Finally, clonal analysis of rearranged immunoglobulin genes performed on microdissected Hodgkin and Reed-Sternberg and mantle cell lymphoma cells provided definite evidence of separate clonal origins of the two tumors in the patients. These EBV-positive, clonally unrelated tumors seem to represent true composite neoplasms, in contrast to cases showing merely clonal progression.

Our findings support the suspicion of another hereditary colorectal syndrome different from HNPCC and characterized by MSS, the normal MMR immunohistochemical expression, the presence of only colorectal tumors, and the absence of individuals with multiple primary tumors. All these circumstances suggest the existence of a non-MMR gene being responsible for this new syndrome.

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