Carlos E. Bacchi

CDX2, a highly sensitive and specific marker of adenocarcinomas of intestinal origin: An immunohistochemical survey of 476 primary and metastatic carcinomas

CDX2 is a recently cloned homeobox gene that encodes an intestine-specific transcription factor, expressed in the nuclei of epithelial cells throughout the intestine, from duodenum to rectum. While expression of CDX2 protein in primary and metastatic colorectal carcinomas has been previously documented, neither the sensitivity nor the specificity of CDX2 expression, as determined by immunohistochemistry, for colorectal adenocarcinoma has been determined. We performed an immunohistochemical survey of 476 tumors with a monoclonal antibody, CDX2–88, including 89 tumors from the colon and duodenum and 95 tumors from other gastrointestinal sites, including the esophagus, stomach, pancreatobiliary system, gastrointestinal carcinoids, and liver. CDX2 was expressed uniformly (that is, in 76–100% of tumor cells) in all but one of the evaluated colorectal and duodenal tumors. High-level expression of CDX2 was also found, however, in mucinous ovarian carcinomas and adenocarcinomas primary to the urinary bladder of which 64% and 100% were positive, respectively. Gastric, gastroesophageal, and pancreatic adenocarcinomas and cholangiocarcinomas all showed similar, heterogeneous patterns of CDX2 expression. Most tumors in each group showed CDX2 expression by a minority of cells, whereas a substantial minority of cases in each group was completely negative and a smaller minority was uniformly positive. Gastrointestinal carcinoids gave similarly varied results, but the majority (58%) was negative. Hepatocellular carcinomas showed no expression of CDX2. Only very rare examples of carcinomas of the genitourinary and gynecologic tracts, breast, lung, and head and neck showed significant levels of CDX2 expression. In this study of primary and metastatic epithelial tumors, uniform CDX2 expression is demonstrated to be an exquisitely sensitive and highly, but incompletely, specific marker of intestinal adenocarcinomas. Compared with villin, a previously described marker of GI adenocarcinomas, CDX2 demonstrated superior sensitivity and comparable specificity. CDX2 expression can be seen, however, in selected non-GI adenocarcinomas such as mucinous ovarian carcinomas and adenocarcinomas of the urinary bladder.

Abdominopelvic Sarcoma of Perivascular Epithelioid Cells. Report of Four Cases in Young Women, One with Tuberous Sclerosis

The perivascular epithelioid cell has been proposed to be the unifying proliferating cell type in a number of lesions such as angiomyolipoma, lymphangiomyomatosis, clear cell “sugar” tumor and renal capsuloma. With the exception of rare examples of angiomyolipoma, they are non-metastasizing. We report four examples of a new member of this family of perivascular epithelioid cell neoplasms that occur in abdominopelvic location and show metastatic properties. The patients, all women, were aged 19 to 41 years (mean, 32), and presented with a tumor mass involving the serosa of the ileum, uterus or pelvic cavity. Morphologically, the tumors were composed of sheets of large polygonal cells with glycogen-rich clear or eosinophilic cytoplasm and moderately pleomorphic nuclei, traversed by a delicate vasculature, mimicking clear cell carcinoma. There were areas of coagulative necrosis and occasional mitotic figures. Intracytoplasmic brown pigment was present in two cases. Spindly cells, smooth muscle and fat were absent. Lymphovascular invasion was present in all, lymph node metastasis was documented in two and metastasis to the ovary was present in one case. Two patients developed widespread metastatic disease after 10 and 28 months from diagnosis. One patient showed the clinical signs of tuberous sclerosis. In spite of the epithelial-like appearance, the tumor cells were negative for epithelial markers but were strongly positive with the melanogenesis-related marker HMB45. Another melanogenesis marker (MART-1) was positive in two cases. Other markers including S-100 protein, vimentin, muscle-specific actin, desmin and chromogranin A were negative. Thus, these tumors are not readily classifiable in the existing schema of known entities, and show overlapping morpho-phenotypic features of clear cell “sugar” tumor of the lung and epithelioid angiomyolipoma. We consider them as sarcomas composed of a pure population of uncommitted perivascular epithelioid cell, that lack modulation toward smooth muscle or adipose cells.

Breast Implant–Associated Anaplastic Large-Cell Lymphoma: Long-Term Follow-Up of 60 Patients

PURPOSE Breast implant-associated anaplastic large-cell lymphoma (ALCL) is a recently described clinicopathologic entity that usually presents as an effusion-associated fibrous capsule surrounding an implant. Less frequently, it presents as a mass. The natural history of this disease and long-term outcomes are unknown. PATIENTS AND METHODS We reviewed the literature for all published cases of breast implant-associated ALCL from 1997 to December 2012 and contacted corresponding authors to update clinical follow-up. RESULTS The median overall survival (OS) for 60 patients was 12 years (median follow-up, 2 years; range, 0-14 years). Capsulectomy and implant removal was performed on 56 of 60 patients (93%). Therapeutic data were available for 55 patients: 39 patients (78%) received systemic chemotherapy, and of the 16 patients (28%) who did not receive chemotherapy, 12 patients opted for watchful waiting and four patients received radiation therapy alone. Thirty-nine (93%) of 42 patients with disease confined by the fibrous capsule achieved complete remission, compared with complete remission in 13 (72%) of 18 patients with a tumor mass. Patients with a breast mass had worse OS and progression-free survival (PFS; P = .052 and P = .03, respectively). The OS or PFS were similar between patients who received and did not receive chemotherapy (P = .44 and P = .28, respectively). CONCLUSION Most patients with breast implant-associated ALCL who had disease confined within the fibrous capsule achieved complete remission. Proper management for these patients may be limited to capsulectomy and implant removal. Patients who present with a mass have a more aggressive clinical course that may be fatal, justifying cytotoxic chemotherapy in addition to removal of implants.

Clinicopathologic and molecular features of 122 Brazilian cases of nodal and extranodal NK/T-cell lymphoma, nasal type, with EBV subtyping analysis

Extranodal natural killer/T-cell lymphoma, nasal type (NK/TCL) is more prevalent in Asia and in some areas of South and Central America, but it is rarely seen in the United States and Europe. In this study, a series of 122 cases of NK/TCL from Brazil was analyzed with respect to clinicopathologic features. Clinical characteristics and geographic distribution were evaluated in 97 cases of nasal/nasopharyngeal region and 23 cases in extranasal sites including 6 nodal cases. Clinical staging and follow-up information was available in a subset of 21 patients. All cases harbored Epstein-Barr virus (EBV), 95% and 85% expressed cytoplasmic CD3 and CD56, respectively, and all cases were positive for at least 1 marker for cytotoxic granules. The global distribution of EBV subtypes showed predominance of strain subtype A, 89%, and subtype B, 11%. No dual infections were detected. TCR-&ggr; TCR-gene rearrangement was observed in 7 cases; all of them extranodal. Three of TCR-&ggr;+ cases showed EBV subtype A. Two TCR-&ggr;+/CD56+ cases showed EBV subtype B. Geographic distribution of NK/TCL showed higher frequency in the southeast and northeast regions of Brazil. Striking differences among geographic regions were seen with the vast majority of EBV subtype B (86%) occurring in the south and southeast regions.

Human Papillomavirus and Epstein-Barr Virus Infection, p53 Expression, and Cellular Proliferation in Laryngeal Carcinoma

Laryngeal carcinomas are aggressive neoplasms with controversial association with the human papillomavirus (HPV) and Epstein-Barr virus (EBV). So far, the impairment of p53 protein function and its impact on cellular proliferation has not been studied adequately in these tumors. In this work, molecular biologic techniques were used to assess the frequency of HPV and EBV in 110 squamous cell carcinomas of the larynx. In addition, accumulation of p53 and Ki-67 cell proliferation antigen expression in malignant cells was assessed by immunohistochemical analysis. High-grade HPV was found in 37.3% of cases, and none had demonstrable EBV infection. Accumulation of p53 was found in 78.2% of the cases, and it was related to a high Ki-67 labeling index and higher histologic grade. The results demonstrate association of HPV with more than one third of laryngeal carcinomas studied, mainly glottic tumors. Tumors with increased cell proliferation were more frequently high grade, with p53 accumulation and lymph node metastasis.

Carcinoma of the collecting ducts of Bellini and renal medullary carcinoma: clinicopathologic analysis of 52 cases of rare aggressive subtypes of renal cell carcinoma with a focus on their interrelationship.

Carcinoma of the collecting ducts of Bellini and renal medullary carcinoma are rare aggressive neoplasms of putative distal nephron origin. First described in 1949, case reports and review articles constitute a major source of information on collecting duct carcinoma, whereas Davis and colleagues and the pediatric tumor registry have contributed the seminal works on renal medullary carcinoma. Here we present a detailed study of collecting duct carcinoma (n=39) and renal medullary carcinoma (n=13), characterizing these rare neoplasms and analyzing their interrelationship. Both collecting duct carcinoma and renal medullary carcinoma exhibited significant similarities, such as predilection for the right kidney, tumor mass with an epicenter in the renal medulla, and a mean size of 7 cm. Overall, both tumors exhibited a poorly differentiated adenocarcinoma histology with desmoplastic stromal response (100%), inflammatory infiltrate (100%), frequent perinephric extension (collecting duct carcinoma: 97%; renal medullary carcinoma: 83%), lymphovascular invasion (100%), intraluminal mucin (collecting duct carcinoma: 42%; renal medullary carcinoma: 73%), high nuclear grade (97%), overlapping immunoreactivity for Ulex europaeus agglutinin 1 (collecting duct carcinoma: 75%; renal medullary carcinoma:55%), CK7 (collecting duct carcinoma: 44%; renal medullary carcinoma: 71%), and high–molecular weight cytokeratin (collecting duct carcinoma: 26%; renal medullary carcinoma: 29%), and nonimmunoreactivity for Ksp-cadherin. Histologically, collecting duct carcinoma frequently had tubular, tubulopapillary, or irregular glandular architecture, whereas renal medullary carcinoma commonly demonstrated islands of anastomosing tubules and cords forming irregular microcystic spaces. Multiple metastases to the lymph nodes, lung, bone, and liver were observed in both categories at presentation (collecting duct carcinoma: 17%; renal medullary carcinoma: 36%). Only patients with organ-confined small tumors were disease free beyond the median survival time. Differential clinical features between collecting duct carcinoma and renal medullary carcinoma included proclivity for younger male individuals of African ancestry with hemoglobin abnormalities and a shorter median survival of 17 weeks (vs. 44 wk for collecting duct carcinoma) for renal medullary carcinoma. The markedly overlapping clinical features, histology, immunophenotype, metastasis patterns, and uniformly aggressive outcome in collecting duct and renal medullary carcinomas suggest that renal medullary carcinoma is a distinctive clinicopathologic subtype within the entity of collecting duct carcinoma. The extremely poor prognosis and ongoing clinical trials with specific therapeutic protocols argue for their accurate distinction from other renal cell carcinoma subtypes.

MUM1/IRF4: A Review.

MUM1/IRF4 protein is a member of the interferon regulatory factor (IRF) family of transcriptional factors initially described as downstream regulators of interferon signaling. The quantity of this factor varies within the hematopoietic system in a lineage and stage-specific way. It is considered to be a key regulator of several steps in lymphoid, myeloid, and dendritic cell differentiation and maturation. MUM1/IRF4 expression is observed in many lymphoid and myeloid malignancies, and may be a promising target for the treatment of some of these neoplasms. We reviewed the literature on MUM1/IRF4, with emphasis on the pathologic aspects of this marker in reactive and malignant hematologic and nonhematologic conditions.

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.

Primary and Secondary T-cell Lymphomas of the Breast: Clinico-pathologic Features of 11 Cases

Breast involvement by non-Hodgkin lymphomas is rare, and exceptional for T-cell lymphomas; we studied the morphologic, immunophenotypic, and clinical features of 11 patients with T-cell non-Hodgkin lymphomas involving the breast. Four cases fulfilled the definition criteria for primary breast lymphomas, 3 females and 1 male, with a median age of 51 years. One primary breast lymphomas was T-cell lymphoma unspecified, other was subcutaneous panniculitis-like T-cell lymphoma, and 2 cases were anaplastic large cell lymphomas. One of the anaplastic large cell lymphoma cases was found surrounding a silicone breast implant and presented as clinically as mastitis; whereas the other case occurred in a man. T-cell lymphoma secondarily involved the breast in 7 patients, all women and 1 bilateral, with a median age of 29 years. These secondary breast lymphomas occurred as part of widespread nodal or leukemic disease. Three patients had adult T-cell leukemia/lymphoma, including the patient with bilateral lesions, 3 others had precursor T-lymphoblastic lymphoma/leukemia, and the other presented with a peripheral-T-cell lymphoma nonotherwise specified type. Breast T-cell lymphomas are very infrequent and are morphologically and clinically heterogeneous.

Geographic variation in Epstein-Barr virus-associated Burkitt's lymphoma in children from Brazil

In developing countries, BL has a strong association with EBV infection during childhood. In South America, the data have shown an EBV association intermediate between that reported in the United States (30%) and that in equatorial Africa (95%). Early age at EBV infection and lower socioeconomic status have been related to increased EBV‐associated BL in developing countries. In Brazil, there are not enough data on childhood BL related to EBV infection. Our aim was to evaluate the clinicopathologic features and EBV association of 44 children with NHL from the state of Rio de Janeiro, situated in the southeast of Brazil. EBV was detected using RNA in situ hybridization in 36 biopsy specimens. DNA from fresh tumor samples and from paraffin‐embedded tissues of patients were analyzed by PCR, in which the first reaction included primers for an EBNA‐2 common region while the nested reaction amplified the region discriminating between EBV types 1 and 2 in separate reactions. EBV was detected in 21 of 29 BLs (72%), and type 1 virus infected the majority of EBV‐positive BLs (18/21). There was a trend for younger age in children with EBV‐positive BL compared to EBV‐negative BL (median age 4 compared to 6 years, respectively; p = 0.056). Our study confirmed that in the southeast of Brazil BL had an intermediate association with EBV. A higher rate of EBV‐associated BL was described in the northeast of Brazil. These differences are probably related to regional socioeconomic status. In conclusion, our study suggests that early infection with EBV in the background of a low socioeconomic condition associated with other environmental factors could contribute to BL in Brazil.