MUC4 Expression in Angiomatoid Fibrous Histiocytoma.

Angiomatoid fibrous histiocytoma (AFH) is a rarely metastasizing neoplasm that typically occurs in the deep dermis and subcutis of the extremities of young patients, characterized by a t(2;22) translocation involving EWSR1 and CREB1. Because of its distinctive histologic features, the diagnosis of AFH is generally straightforward, although the immunohistochemistry (IHC) findings are relatively nonspecific. We recently encountered a case of primary cranial AFH that showed strong MUC4 IHC expression, which has not yet been reported previously. Prompted by this surprising finding, we investigated MUC4 expression in a series of AFH to evaluate this potential diagnostic pitfall. The expression of ALK by IHC, recently discovered in AFH, was also assessed in this study. We also analyzed EWSR1 rearrangement by fluorescence in situ hybridization using a dual color break-apart probe to confirm the diagnosis. The results showed MUC4 expression in 22.2% of AFH cases (4/18 cases), demonstrating a variable intensity of cytoplasmic staining. Most notably, one of the positive cases showed strong and diffuse expression. ALK IHC expression was observed in 17 of 18 cases (94.4%), usually in a diffuse and strong cytoplasmic pattern. EWSR1 rearrangement was demonstrated by fluorescence in situ hybridization in 81.2% of cases (13 of 16), including all the MUC4-positive cases. Our results indicate that although the significance of MUC4 expression in AFH is unknown, it is important to be aware that a subset of AFH can express the protein by IHC, expanding a variety of MUC4-positive mesenchymal tumors.

Geographic differences in the distribution of molecular subtypes of breast cancer in Brazil.

BACKGROUND: To compare the distribution of the intrinsic molecular subtypes of breast cancer based on immunohistochemical profile in the five major geographic regions of Brazil, a country of continental dimension, with a wide racial variation of people. METHODS: The study was retrospective observational. We classified 5,687 invasive breast cancers by molecular subtype based on immunohistochemical expression of estrogen-receptor (ER), progesterone-receptor (PR), human epidermal growth factor receptor 2 (HER2), and Ki-67 proliferation index. Cases were classified as luminal A (ER and/or PR positive and HER2 negative, Ki-67 < 14%), luminal B (ER and/or PR positive, HER2 negative, and Ki-67 > 14%), triple-positive (ER and/or PR positive and HER2 positive), HER2-enriched (ER and PR negative, and HER2- positive), and triple-negative (TN) (ER negative, PR negative, and HER2- negative). Comparisons of the ages of patients and molecular subtypes between different geographic regions were performed. RESULTS: South and Southeast regions with a higher percentage of European ancestry and higher socioeconomic status presented with the highest proportion of luminal tumors. The North region presented with more aggressive subtypes (HER2-enriched and triple-negative), while the Central-West region predominated triple-positive carcinomas. The Northeast--a region with a high African influence--presented intermediate frequency of the different molecular subtypes. The differences persisted in subgroups of patients under and over 50 years. CONCLUSIONS: The geographic regions differ according to the distribution of molecular subtypes of breast cancer. However, other differences, beside those related to African ancestry, such as socioeconomic, climatic, nutritional, and geographic, have to be considered to explain our results. The knowledge of the differences in breast cancer characteristics among the geographic regions may help to organize healthcare programs in large countries like Brazil with diverse economic and race composition among different geographic regions.

The contribution of HGAL/GCET2 in immunohistological algorithms: a comparative study in 424 cases of nodal diffuse large B-cell lymphoma.

Diffuse large B-cell lymphoma can be subclassified into at least two molecular subgroups by gene expression profiling: germinal center B-cell like and activated B-cell like diffuse large B-cell lymphoma. Several immunohistological algorithms have been proposed as surrogates to gene expression profiling at the level of protein expression, but their reliability has been an issue of controversy. Furthermore, the proportion of misclassified cases of germinal center B-cell subgroup by immunohistochemistry, in all reported algorithms, is higher compared with germinal center B-cell cases defined by gene expression profiling. We analyzed 424 cases of nodal diffuse large B-cell lymphoma with the panel of markers included in the three previously described algorithms: Hans, Choi, and Tally. To test whether the sensitivity of detecting germinal center B-cell cases could be improved, the germinal center B-cell marker HGAL/GCET2 was also added to all three algorithms. Our results show that the inclusion of HGAL/GCET2 significantly increased the detection of germinal center B-cell cases in all three algorithms (P<0.001). The proportions of germinal center B-cell cases in the original algorithms were 27%, 34%, and 19% for Hans, Choi, and Tally, respectively. In the modified algorithms, with the inclusion of HGAL/GCET2, the frequencies of germinal center B-cell cases were increased to 38%, 48%, and 35%, respectively. Therefore, HGAL/GCET2 protein expression may function as a marker for germinal center B-cell type diffuse large B-cell lymphoma. Consideration should be given to the inclusion of HGAL/GCET2 analysis in algorithms to better predict the cell of origin. These findings bear further validation, from comparison to gene expression profiles and from clinical/therapeutic data.

Hodgkin's lymphoma presenting as dominant gastric lesion in immunocompetent patients: report of 5 cases with EBV analysis.

Primary Hodgkin's lymphoma (HL) of the stomach is an extremely rare entity. Most cases of gastric involvement by HL are observed in the setting of disseminated disease. The nonspecific nature of the symptoms and endoscopic findings, which include a large malignant-looking ulcer and mass or wall thickening, together with the considerable histological overlap between HLs and some non-HLs or undifferentiated carcinoma, make the surgical resection diagnosis extremely difficult. An accurate diagnosis is important as treatment and outcome differ significantly for these neoplasms. In small endoscopic gastric biopsies and even in postoperative specimens, the precise histological diagnosis of HL is particularly challenging. Here, the authors report 5 cases of 2 women and 3 men aged 22 to 68, with gastric involvement by classic HLs-3 primary gastric HLs and 2 as part of widespread disease. All 5 patients presented with digestive symptoms. At endoscopy, the lesions presented as ulcerated and elevated lesions, with or without mucosal thickening. Four patients were misdiagnosed in the preoperative biopsy or in the gastrectomy specimen. Association with Epstein-Barr virus (EBV) was detected in 4 cases, with a predominance of subtype A EBV. These cases illustrate the significant difficulties, both clinical and pathological, in achieving the diagnosis of HL involving the stomach in immunocompetent patients.

Triple-negative breast carcinomas are a heterogeneous entity that differs between young and old patients.

OBJECTIVE: To compare the frequency and immunohistochemical profiles of triple-negative breast carcinomas in younger and older women. METHODS AND RESULTS: We selected patients diagnosed with triple-negative breast carcinomas. The groups examined were women who were 35 years old or younger between 1997 and 2007 (n = 74) and, for comparison, women who were 60 years old or older (n = 19, consecutive cases). All formalin-fixed and paraffin-embedded tumor samples were reviewed and immunohistochemically stained for ER, PR, HER2, Ki-67 antigen, epidermal growth factor receptor, cytokeratin 5/6, p53, vimentin, CD117, and p63 using tissue microarrays blocks. Triple-negative breast carcinomas corresponded to 34.6% (74/213) of the carcinomas from the younger patients and 16.2% (19/117) of the carcinomas from the older patients (p = 0.002). No significant differences in the frequency of the basal phenotype were observed in the two patient groups based on CK5/6 and/or epidermal growth factor receptor expression (74.3% vs. 68.4%). However, triple-negative breast carcinomas in the older patients presented a higher frequency of CK5/6 expression compared to those of younger patients (42.1% vs. 9.6%; p = 0.005), whereas triple-negative breast carcinomas of younger patients had a higher expression level of epidermal growth factor receptor (71.6% vs. 47.3%). CONCLUSIONS: These results show that there were significant molecular differences between the triple-negative basal-like breast carcinomas that were diagnosed in younger women and those that were diagnosed in older women. These findings may provide a basis for describing the more aggressive phenotype of the triple-negative breast carcinomas observed in younger women.

DOG1 for the diagnosis of gastrointestinal stromal tumor (GIST): Comparison between 2 different antibodies.

Gastrointestinal stromal tumor (GIST) is the most common mesenchymal neoplasm of the gastrointestinal tract. Discovered on GIST-1 (DOG1) is a recently described protein expressed in GISTs irrespective of mutation status. The aim of this study was to investigate the immunohistochemical expression of DOG1 using 2 different monoclonal antibodies (DOG1.1 and the commercially available K9 antibody) in 668 GIST cases and to compare the results with the expression of KIT. DOG1 and KIT expression also were studied in most human normal tissues and several nonmesenchymal and mesenchymal tumors other than GIST. KIT was expressed in 643 (96.3%) GISTs. DOG1.1 and K9 were positive in 538 (80.5%) and 642 (96.1%) GIST cases, respectively. In 25 (3.7%) KIT-negative GIST cases, DOG1 was expressed in 5 (20.0%) and 19 (76.0%) using DOG1.1 and K9 antibodies, respectively. Only 0.9% of GISTs were negative for KIT, DOG1.1, and K9. Most normal human tissues did not reveal KIT and DOG1 expression. DOG1.1 was positive in only 2 of 57 synovial sarcomas and 1 of 61 soft tissue leiomyosarcomas. K9 was positive in 5 of 57 synovial sarcomas, 1 of 14 angiosarcomas, 1 of 61 soft tissue leiomyosarcomas, 3 of 4 adenoid cystic carcinomas of the head and neck, and in myoepithelial cells of 9 of 11 fibroadenomas of the breast. In conclusion, the commercially available K9 is of great utility for the diagnosis of most KIT-negative GISTs, and the combination of both KIT and K9 antibody in a panel of immunohistochemistry can define the diagnosis of GIST in more than 99% of cases.

Triple-negative breast carcinomas are a heterogeneous entity that differs between young and old patients

OBJECTIVE: To compare the frequency and immunohistochemical profiles of triple-negative breast carcinomas in younger and older women. METHODS AND RESULTS: We selected patients diagnosed with triple-negative breast carcinomas. The groups examined were women who were 35 years old or younger between 1997 and 2007 (n = 74) and, for comparison, women who were 60 years old or older (n = 19, consecutive cases). All formalin-fixed and paraffin-embedded tumor samples were reviewed and immunohistochemically stained for ER, PR, HER2, Ki-67 antigen, epidermal growth factor receptor, cytokeratin 5/6, p53, vimentin, CD117, and p63 using tissue microarrays blocks. Triple-negative breast carcinomas corresponded to 34.6 percent (74/213) of the carcinomas from the younger patients and 16.2 percent (19/117) of the carcinomas from the older patients (p = 0.002). No significant differences in the frequency of the basal phenotype were observed in the two patient groups based on CK5/6 and/or epidermal growth factor receptor expression (74.3 percent vs. 68.4 percent). However, triple-negative breast carcinomas in the older patients presented a higher frequency of CK5/6 expression compared to those of younger patients (42.1 percent vs. 9.6 percent; p = 0.005), whereas triplenegative breast carcinomas of younger patients had a higher expression level of epidermal growth factor receptor (71.6 percent vs. 47.3 percent). CONCLUSIONS: These results show that there were significant molecular differences between the triple-negative basal-like breast carcinomas that were diagnosed in younger women and those that were diagnosed in older women. These findings may provide a basis for describing the more aggressive phenotype of the triple-negative breast carcinomas observed in younger women.

Autoimmune lymphoproliferative syndrome in a patient with a new minimal deletion in the death domain of the FAS gene.

We present a case of autoimmune lymphoproliferative syndrome (ALPS) caused by a previously undescribed minimal deletion in the death domain of the FAS gene. ALPS is an uncommon disease associated with an impaired Fas-mediated apoptosis. The patient presented with a history of splenomegaly since 4 months of age, associated with cervical lymphadenopathy, which improved with oral corticosteroid treatment. Relevant laboratory findings were the presence of anemia, thrombocytopenia, and positive direct and indirect Coombs tests. He was not an offspring of consanguineous parents. Two cervical lymph node biopsies were performed, at 4 years and at 6 years of age. In both lymph nodes, there was marked paracortical expansion by lymphocytes in variable stages of immunoblastic transformation and a very high cell proliferating index. Some clear cells were also present, raising the suspicion of malignant lymphoma. In one of the lymph nodes, there was also a focus rich in large histiocytes with round nuclei and emperipolesis, consistent with focal Rosai-Dorfman disease. Immunostaining showed numerous CD3+ cells, many of which were double-negative (CD4- CD8-) and expressed CD57, especially around the follicles. Molecular studies of the lymph node biopsy showed a point deletion (4-base pair deletion) in exon 9 of the FAS gene (930del TGCT), which results in 3 missense amino acids.