A New Face of Fibrin-Associated Large B-Cell Lymphoma: Epstein-Barr Virus-Positive Breast Implant-Associated Diffuse Large B-Cell Lymphoma.

Recently, there have been reports of what could be a new lymphoproliferative entity: breast implant-associated Epstein-Barr virus positive (EBV+) diffuse large B-cell lymphoma (EBV+ BIA-DLBCL). The new World Health Organization classification has categorized it as fibrin-associated large B-cell lymphomas (FA-LBCLs); therefore, it could be referred to as breast implant-associated fibrin-associated large B-cell lymphomas (BIA-FA-LBCLs). Although the association between breast implants and lymphomas has been known since the mid-1990s, it has been almost exclusively breast implant-associated anaplastic large cell lymphoma (BIA-ALCL). Here, we describe the first case of BIA-FA-LBCL at our center, with a literature review of the clinical features, diagnosis and treatment approach of this lymphoma. We also explore the differential diagnosis of BIA-FA-LBCL, highlighting the diagnostic challenges and the reasons that have led these lymphomas to being labeled as a new face of FA-LBCL.

Decoding the molecular heterogeneity of pediatric monomorphic post-solid organ transplant lymphoproliferative disorders.

Posttransplant lymphoproliferative disorders (PTLDs) represent a broad spectrum of lymphoid proliferations, frequently associated with Epstein-Barr virus (EBV) infection. The molecular profile of pediatric monomorphic PTLDs (mPTLDs) has not been elucidated, and it is unknown whether they display similar genetic features as their counterpart in adult and immunocompetent (IMC) pediatric patients. In this study, we investigated 31 cases of pediatric mPTLD after solid organ transplantation, including 24 diffuse large B-cell lymphomas (DLBCLs), mostly classified as activated B cell, and 7 cases of Burkitt lymphoma (BL), 93% of which were EBV positive. We performed an integrated molecular approach, including fluorescence in situ hybridization, targeted gene sequencing, and copy number (CN) arrays. Overall, PTLD-BL carried mutations in MYC, ID3, DDX3X, ARID1A, or CCND3 resembling IMC-BL, higher mutational burden than PTLD-DLBCL, and lesser CN alterations than IMC-BL. PTLD-DLBCL showed a very heterogeneous genomic profile with fewer mutations and CN alterations than IMC-DLBCL. Epigenetic modifiers and genes of the Notch pathway were the most recurrently mutated in PTLD-DLBCL (both 28%). Mutations in cell cycle and Notch pathways correlated with a worse outcome. All 7 patients with PTLD-BL were alive after treatment with pediatric B-cell non-Hodgkin lymphoma protocols, whereas 54% of patients with DLBCL were cured with immunosuppression reduction, rituximab, and/or low-dose chemotherapy. These findings highlight the low complexity of pediatric PTLD-DLBCL, their good response to low-intensity treatment, and the shared pathogenesis between PTLD-BL and EBV-positive IMC-BL. We also suggest new potential parameters that could help in the diagnosis and the design of better therapeutic strategies for these patients.

Proteomics Characterization of Clear Cell Renal Cell Carcinoma.

PURPOSE: To explore the tumor proteome of patients diagnosed with localized clear cell renal cancer (ccRCC) and treated with surgery. MATERIAL AND METHODS: A total of 165 FFPE tumor samples from patients diagnosed with ccRCC were analyzed using DIA-proteomics. Proteomics ccRCC subtypes were defined using a consensus cluster algorithm (CCA) and characterized by a functional approach using probabilistic graphical models and survival analyses. RESULTS: We identified and quantified 3091 proteins, including 2026 high-confidence proteins. Two proteomics subtypes of ccRCC (CC1 and CC2) were identified by CC using the high-confidence proteins only. Characterization of molecular differences between CC1 and CC2 was performed in two steps. First, we defined 514 proteins showing differential expression between the two subtypes using a significance analysis of microarrays analysis. Proteins overexpressed in CC1 were mainly related to translation and ribosome, while proteins overexpressed in CC2 were mainly related to focal adhesion and membrane. Second, a functional analysis using probabilistic graphical models was performed. CC1 subtype is characterized by an increased expression of proteins related to glycolysis, mitochondria, translation, adhesion proteins related to cytoskeleton and actin, nucleosome, and spliceosome, while CC2 subtype showed higher expression of proteins involved in focal adhesion, extracellular matrix, and collagen organization. CONCLUSIONS: ccRCC tumors can be classified in two different proteomics subtypes. CC1 and CC2 present specific proteomics profiles, reflecting alterations of different molecular pathways in each subtype. The knowledge generated in this type of studies could help in the development of new drugs targeting subtype-specific deregulated pathways.

Case Report: Combined Liver-Kidney Transplantation to Correct a Mutation in Complement Factor B in an Atypical Hemolytic Uremic Syndrome Patient.

Pathogenic gain-of-function variants in complement Factor B were identified as causative of atypical Hemolytic Uremic syndrome (aHUS) in 2007. These mutations generate a reduction on the plasma levels of complement C3. A four-month-old boy was diagnosed with hypocomplementemic aHUS in May 2000, and he suffered seven recurrences during the following three years. He developed a severe hypertension which required 6 anti-hypertensive drugs and presented acrocyanosis and several confusional episodes. Plasma infusion or exchange, and immunosuppressive treatments did not improve the clinical evolution, and the patient developed end-stage renal disease at the age of 3 years. Hypertension and vascular symptoms persisted while he was on peritoneal dialysis or hemodialysis, as well as after bilateral nephrectomy. C3 levels remained low, while C4 levels were normal. In 2005, a heterozygous gain-of-function mutation in Factor B (K323E) was found. A combined liver and kidney transplantation (CLKT) was performed in March 2009, since there was not any therapy for complement inhibition in these patients. Kidney and liver functions normalized in the first two weeks, and the C3/C4 ratio immediately after transplantation, indicating that the C3 activation has been corrected. After remaining stable for 4 years, the patient suffered a B-cell non-Hodgkin lymphoma that was cured by chemotherapy and reduction of immunosuppressive drugs. Signs of liver rejection with cholangitis were observed a few months later, and a second liver graft was done 11 years after the CLKT. One year later, the patient maintains normal kidney and liver functions, also C3 and C4 levels are within the normal range. The 12-year follow-up of the patient reveals that, in spite of severe complications, CLKT was an acceptable therapeutic option for this aHUS patient.

Histopathological Subtypes and PD-L1 Expression in Primary Urethral Adenocarcinoma: A Series of 5 Cases.

BACKGROUND AND OBJECTIVES: Urethral adenocarcinoma is a rare disease with poor prognosis that can display multiple histologic patterns and has an unclear histogenesis. Radical surgery with extensive periurethral resection is the preferred therapeutic approach. Both chemotherapy and radiotherapy have been used as complementary treatment options. Due to the tendency of these tumors to recur, treatment-associated complications, and the limited choice of therapeutic options, patient management can be difficult. Given the lack of literature regarding immunotherapy in urethral adenocarcinoma, our objective was to explore the expression of programmed death receptor-ligand 1 (PD-L1) throughout the different histological subtypes of primary urethral adenocarcinoma. METHODS: We reviewed all primary urethral adenocarcinomas diagnosed at our hospital between 1965 and 2019, performed immunohistochemical assays on the tissue blocks, classified them according to their histology and origin, and performed PD-L1 (22C3) immunohistochemistry assays in all cases. RESULTS: We found a total of 5 cases of primary urethral adenocarcinoma. All of the patients were women. One of the cases was a cribriform adenocarcinoma, 2 were columnar-mucinous adenocarcinomas, and 2 were clear cell adenocarcinomas. One of the clear cell adenocarcinomas strongly expressed PD-L1. In addition, a profuse inflammatory infiltration constituted by CD3-positive and CD8-positive T lymphocytes within tumor cells was observed in this case. None of the other cases showed PD-L1 expression. CONCLUSIONS: In conclusion, some urethral adenocarcinomas may strongly express PD-L1 and thus could potentially allow the use of immunotherapy in selected cases of advanced or recurrent adenocarcinoma.

A case-control study to assess the role of polyomavirus in transplant complications: Where do we stand?

PURPOSE: The study's aim was to assess whether polyomavirus DNAemia screening was associated with different outcomes in patients with positive viremia compared with negative viremia. METHODS: Case-control retrospective study of patients with polyomavirus DNAemia (viremia > 1000 copies/mL) matched 1:1 with controls. Control group consists of the patient who received a transplant immediately before or after each identified case and did have nil viremia. FINDING: Ultimately, 120 cases of BK polyomavirus (BKPyV) were detected and matched with 130 controls. Of these, 54 were adult kidney transplant recipients (KTRs), 43 were pediatric KTRs, and 23 were undergoing hemato-oncologic therapy, of which 20 were undergoing hematopoietic stem cell transplantation. The odds ratio (OR) for overall risk of poorer outcomes in cases versus controls was 16.07 (95% CI: 5.55-46.54). The unfavorable outcome of switching the immunosuppressive drug (ISD) (14/40,35%) was no different from that of those treated with reduced ISD doses (31/71, 43.6%, P = .250). Acute rejection or graft-versus-host disease, previous transplant, and intensity of immunosuppression (4 ISDs plus induction or conditioning) were risk factors for BKPyV-DNAemia (OR: 13.96, 95% CI: 11.25-15.18, P < .001; OR: 6.14, 95% CI: 3.91-8.80, P < .001; OR: 5.53, 95% CI: 3.37-7.30, P < .001, respectively). CONCLUSIONS: Despite viremia screening, dose reduction, and change in therapeutic protocol, patients with positive BKPyV-DNAemia present poorer outcomes and unfavorable results.

Molecular and clinicopathologic characterization of intravenous leiomyomatosis.

Intravenous leiomyomatosis (IVL) is an unusual uterine smooth muscle proliferation that can be associated with aggressive clinical behavior despite a histologically benign appearance. It has some overlapping molecular characteristics with both uterine leiomyoma and leiomyosarcoma based on limited genetic data. In this study, we assessed the clinical and morphological characteristics of 28 IVL and their correlation with molecular features and protein expression, using array comparative genomic hybridization (aCGH) and Cyclin D1, p16, phosphorylated-Rb, SMARCB1, SOX10, CAIX, SDHB and FH immunohistochemistry. The most common morphologies were cellular (n = 15), usual (n = 11), and vascular (n = 5; including 3 cellular IVL showing both vascular and cellular features). Among the immunohistochemical findings, the most striking was that all IVL showed differential expression of either p16 or Cyclin D1 in comparison to surrounding nonneoplastic tissue. Cytoplasmic phosphorylated-Rb was present in all but one IVL with hyalinization. SMARCB1, FH, and SDHB were retained; S0X10 and CAIX were not expressed. The most common genetic alterations involved 1p (39%), 22q (36%), 2q (29%), 1q (25%), 13q (21%), and 14q (21%). Hierarchical clustering analysis of recurrent aberrations revealed three molecular groups: Groups 1 (29%) and 2 (18%) with associated del(22q), and Group 3 (18%) with del(10q). The remaining IVL had nonspecific or no alterations by aCGH. Genomic index scores were calculated for all cases and showed no significant difference between the 14 IVL associated with aggressive clinical behavior (extrauterine extension or recurrence) and those without (median scores 5.15 vs 3.5). Among the 5 IVL associated with recurrence, 4 had a vascular morphology and 3 had alterations of 8q. Recurrent chromosome alterations detected herein overlap with those observed in the spectrum of uterine smooth muscle tumors and involve genes implicated in mesenchymal tumors at different sites with distinct morphological features.

Challenging Diagnosis of a Solitary Retroperitoneal Mass: A Case Report of Castleman's Disease and Review of the Literature.

Castleman's disease (CD) is an uncommon type of lymphoproliferative disorder. Its etiology and prevalence are unclear. The retroperitoneum is a very rare site for presentation of the unicentric variant, where it mimics malignant tumors. A 59-year-old man is referred to the urology outpatient clinic for the study of microhematuria found in a routine analysis. CT scan of the abdomen identified a solid, circumscribed mass, measuring 28 × 30 × 31 mm in the left para-aortic zone, with homogeneous contrast enhancement. Excisional surgery and regional lymphadenectomy were performed via laparoscopy. Postoperative course concurred without incidences. Histological diagnosis confirmed unicentric CD, hyaline-vascular type. CD is a rare entity, and the unicentric type presents as an asymptomatic mass. Retroperitoneum is a rare localization, where initial imaging diagnosis is unclear and surgical resection is the preferred treatment.

Lipomatosis cardiaca masiva, hallazgo en la autopsia de un paciente con muerte súbita / Massive cardiac lipomatosis, an autopsy finding in a patient with sudden death

La sustitución grasa de las células miocárdicas es un proceso degenerativo que afecta en mayor medida al ventrículo derecho y se encuentra en el 50% de las personas ancianas. El problema se origina cuando esta degeneración se produce en grado masivo, planteando la necesidad de realizar el diagnóstico diferencial con otras enfermedades. Se presenta el caso de un paciente que falleció de forma súbita y en su autopsia se encontró esta dolencia como única explicación del desenlace (AU)

The fat replacement of myocardial cells is a degenerative process that usually affects the right ventricle and is found in 50% of the elderly. The problem arises when this degeneration occurs to a massive degree, a differential diagnosis with other pathologies being necessary. We present the case of a patient who died suddenly and a massive cardiac lipomatosis was found on autopsy, as the only explanation of the outcome (AU)

[Massive cardiac lipomatosis, an autopsy finding in a patient with sudden death]. / Lipomatosis cardiaca masiva, hallazgo en la autopsia de un paciente con muerte súbita.

The fat replacement of myocardial cells is a degenerative process that usually affects the right ventricle and is found in 50% of the elderly. The problem arises when this degeneration occurs to a massive degree, a differential diagnosis with other pathologies being necessary. We present the case of a patient who died suddenly and a massive cardiac lipomatosis was found on autopsy, as the only explanation of the outcome.

Carcinomas adenoescamosos y escamosos de colon y recto / Adenosquamous and squamous carcinomas of the colon and rectum

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Apoptosis-related proteins are potential markers of neonatal hypoxic-ischemic encephalopathy (HIE) injury.

Neonatal hypoxic-ischemic encephalopathy (HIE) causes high mortality and long-term morbidity rates. The magnitude of the neuronal damage depends on the duration and severity of the initial insult combined with the deleterious effects of reperfusion and apoptosis. Currently, a diagnosis of HIE is based largely on the neurological and histological findings. Therefore, the aim of this study was to identify apoptosis-related proteins that might serve as potential markers of HIE injury. As an initial step toward reaching this objective, we analyzed changes in protein levels in an in vitro model of hypoxia using antibody arrays, and we have identified changes in the expression level of two proteins involved in apoptosis, Smac-DIABLO and cathepsin D. We obtained brain sections from eight neonatal HIE patients and performed histological staining, TUNEL assays and Smac-DIABLO and cathepsin D immunolocalization. Our results revealed a high number of TUNEL-positive cells, including neurons, astrocytes and ependymal cells, in the various regions that were analyzed. Interestingly, many of the areas that were positive for TUNEL staining did not appear to be damaged in the histological evaluation. In addition, using immunostaining, we found that Smac-DIABLO and cathepsin D had the same regional distribution pattern. Taken together, these findings indicate that these two proteins could serve as markers to identify injured regions that might not to be detectable using histological observations alone.

Atypical clinical presentation and long-term survival in a patient with optic nerve medulloepithelioma: a case report.

INTRODUCTION: Medulloepithelioma is a rare congenital tumor of the primitive medullary neuroepithelium. A significant proportion of patients with medulloepithelioma arising from the optic nerve die from intracranial spread or cerebral metastasis. Because it has no known distinct clinical features and because of its low frequency, this tumor presents within the first two to six years of life and is usually misdiagnosed clinically as a different type of optic nerve tumor. Here, we describe a new and atypical case of medulloepithelioma of the optic nerve in a 12-year-old boy. To the best of our knowledge, he is the oldest reported patient to present with this disease and, now as an adult, has the longest documented period of disease-free survival. CASE PRESENTATION: A 12-year-old Caucasian boy with headache and unilateral amaurosis was referred for a presumed optic nerve glioma to our hospital. A computed tomography scan showed optic nerve enlargement, and fundoscopy showed a whitish mass at the optic disc. Our patient had been followed at his local hospital for four years for an 'optic disc cyst' with no change or progression. He experienced mild progressive visual impairment during that period. He was admitted for resection, and a histopathological analysis revealed a medulloepithelioma of the optic nerve. Supplemental orbital radiotherapy was performed. He remained disease-free for 25 years. CONCLUSIONS: Medulloepithelioma of the optic nerve can clinically mimic more common pediatric tumors, such as optic glioma, meningioma, or retinoblastoma. Thus, medulloepithelioma should be included in the differential diagnoses of pediatric optic nerve lesions. Fundoscopy in these patients may provide relevant information for diagnosis. Anterior optic nerve medulloepitheliomas may behave differently from and have a better prognosis than medulloepitheliomas that have a more posterior location. Our case report illustrates that long-term survival can be achieved in patients with this malignant tumor.

Valoración anatomopatológica e inmunohistoquímica frente a Treponema pallidum en 42 biopsias con sospecha clinicopatológica de sífilis / Pathological and immunohistochemical evalution of Treponema pallidum in 42 biopsies from cases of suspected syphilis

La sífilis es una enfermedad de transmisión sexual que aún es relativamente frecuente y cuyo diagnóstico se ha basado tradicionalmente en pruebas serológicas. La histopatología de sus lesiones, especialmente en la sífilis secundaria, puede ser muy variable. La detección de Treponema pallidum en biopsias se ha realizado hasta fechas recientes mediante técnicas de impregnación argéntica, que presentan escasa sensibilidad. Desde hace unos años se dispone de detección inmunohistoquímica frente a espiroquetas. Éste es un trabajo de revisión de 42 biopsias con sospecha clínica y/o anatomopatológica de sífilis en los que se valoran sus hallazgos morfopatológicos e inmunohistoquímicos, con especial orientación al secundarismo luético, que mostró una positividad inmunohistoquímica del 83,3%(AU)

Syphilis is a sexually transmitted disease which is still common. Traditionally, serology has been the diagnostic gold standard. The pathology of the lesions, especially those of secondary syphilis, can vary. Spirochetes (Treponema pallidum) can be detected with silver staining, but with only low sensitivity. Since the 1990s, immunohistochemistry against Treponema has been available. The pathology and immunohistochemistry of 42 biopsies from patients with a possible clinical diagnosis of syphilis were examined. In secondary syphilis, treponemas were detected in 83.3% of the cases using immunohistochemistry(AU)

Aurora B kinase expression in laryngeal squamous cell carcinoma and its prognostic implications.

AIMS: To investigate the clinical and prognostic significance of Aurora B in laryngeal squamous cell carcinomas (LSCC). METHODS AND RESULTS: Aurora B protein expression was analysed in 259 LSCC. The proliferation index (Ki67) and the expression of other cell cycle control proteins, such as Aurora A, survivin and p53 was also determined. Aurora B was highly expressed in 55.4% of LSCC. High Aurora B expression levels were correlated with tumour recurrence (P=0.01), death from disease (P=0.05) and decreased disease-free survival (P=0.013) and overall survival (P=0.04). Survivin expression was neither associated with clinicopathological characteristics nor with survival. However, survivin expression in the nucleus paralleled Aurora B expression (P=0.014). Aurora A expression was associated significantly with increased tumour grade (P=0.008). Multivariate analysis indicated that Aurora B was an independent predictor for LSCC-specific disease-free survival [hazard ratio (HR), 2.10; 95% confidence interval (95% CI), 1.25-3.52 (P=0.005)] and overall survival [HR, 1.91; 95% CI 1.01-3.34 (P=0.023)]. CONCLUSIONS: Aurora B may be a novel prognostic biomarker for LSCC and a potential therapeutic target in this type of tumour.

Malignant teratoma of the thyroid in a pregnant woman.

Most teratomas involving the thyroid gland are benign and occur in children. However, the adult cases reported are mostly malignant. Many of the cases previously described in the medical literature have fatal outcome because of spread of the tumor refractory to treatment. We report a case of primary malignant teratoma of the thyroid in a 38-year-old pregnant black woman. She was treated with a combination of surgery, and postoperative chemotherapy with good initial response.