Frequency of CDH1, CTNNA1 and CTNND1 Germline Variants in Families with Diffuse and Mixed Gastric Cancer.

The most well-characterized hereditary form of gastric cancer is hereditary diffuse gastric cancer (HDGC), an autosomal dominant syndrome characterized by an increased risk of diffuse gastric and lobular breast cancer. HDGC is predominantly caused by germline pathogenic variants in the CDH1 gene, and more rarely in the CTNNA1 gene. Furthermore, the International Gastric Cancer Linkage Consortium (IGCLC) guidelines do not clarify whether or not mixed gastric cancer (with a diffuse component) should be considered in the HDGC genetic testing criteria. We aimed to evaluate the contribution of CTNNA1 and CTNND1 germline variants to HDGC. Additionally, we also intended to compare the frequencies of CDH1 and CTNNA1 (and eventually CTNND1) germline variants between patients with diffuse and mixed gastric carcinomas to evaluate if genetic testing for these genes should or should not be considered in patients with the latter. We analyzed the CDH1 gene in 67 cases affected with early-onset/familial mixed gastric carcinomas and the CTNNA1 and CTNND1 genes in 208 cases with diffuse or mixed gastric cancer who had tested negative for CDH1 pathogenic germline variants. A deleterious CTNNA1 germline variant was found in 0.7% (1/141) of diffuse gastric cancer patients meeting the 2020 IGCLC criteria, as compared to the rate of 2.8% of CDH1 deleterious variants found by us in this setting. No deleterious variants were found in CTNND1, but six variants of uncertain significance were identified in this gene. We did not find any pathogenic CDH1, CTNNA1 or CTNND1 variant in index patients with early-onset/familial mixed gastric cancer, so there is no evidence that supports including this tumor type in the testing criteria for germline variants in these genes. The role of the CTNND1 gene in inherited gastric cancer predisposition is still unclear.

Composite pheochromocytoma of the adrenal gland-a review of published cases.

Composite pheochromocytoma (CP) is a rare adrenal tumor, composed of ordinary pheochromocytoma and neuroblastic components. There is a paucity of information in the literature regarding this entity. We report the case of a 56-year-old woman with a CP of the left adrenal gland with a ganglioneuroma component. A review of the published literature found 110 cases of CP. The median age was 51.5 (5.86) years, and 59/110 (53.6%) were female. Association with genetic predisposition syndromes was found in 22/110 (20%), the most common of which was neurofibromatosis type 1, in 15/110 (13.6%). The most common histologic type of the neuroblastic component was ganglioneuroma in 83/110 (75.5%). Twenty-seven cases reported SDHB immunohistochemistry results; none of which was positive. Nine patients (8.2%) presented/developed metastatic disease, and 9 patients (8.2%) died from disease. To our knowledge, this is the largest review describing clinical, histopathological, molecular, and prognostic features of CP.

Not a neuroendocrine tumor: A case of hepatocellular carcinoma in ectopic liver tissue in the pancreas.

Hepatocellular carcinoma (HCC) accounts for most of the hepatic neoplasms and can also occur in ectopic liver tissue. We present a case of a 55-year-old male complaining of weight loss. The imaging studies reported a 2.9 cm nodule in the pancreatic body, with a neuroendocrine tumor diagnosis by cytology. A corpo-caudal pancreatectomy was performed. Pathology showed a well-differentiated HCC developed in ectopic liver tissue with free margins and no lymph node metastases. HCC presenting in ectopic liver tissue is rare. In this case, the preoperative study did not establish the diagnosis, warranting the need for suspicion of this neoplasm.

Not Always a Thymoma - About a Mediastinal Cavernous Hemangioma.

A mediastinal cavernous hemangioma is difficult to distinguish from other types of mediastinal tumours. They are usually asymptomatic and incidentally discovered in an imaging study but can present with compressive symptoms or by infiltration of adjacent structures. A 64-year-old woman with a prior history of triple negative invasive carcinoma of the breast, under surveillance was referred after a Chest CT-scan showed a soft tissue 40x20 mm mediastinal mass, suggestive of a thymoma, and as such no tissue biopsy was obtained. A right-side uniportal VATS was performed, the anterior mediastinum dissected and the mass was exposed, and several anomalous veins were identified. Histopathology showed 36x31x15 mm mass, compatible with a cavernous hemangioma of the anterior mediastinum. This case, whilst not questioning the NCCN statement suggesting not doing a tissue biopsy, points to the fact that rare differential diagnosis, like a Cavernous Hemangioma do exist, and a careful and sound judgement is needed at all times.

Diagnosis of MALT Lymphoma from Surveillance Endoscopy of a Patient with a CDH1 Gene Germline Mutation.

Carriers of the mutated CDH1 gene have an increased risk of developing early-onset signet-ring cell (diffuse) gastric cancer. We present a case of a young patient with a confirmed mutation of the CDH1 gene, who was diagnosed with a gastric marginal zone B-cell lymphoma (MZL) of mucosa-associated lymphoid tissue (MALT lymphoma) from surveillance endoscopy. He underwent Helicobacter pylori eradication treatment and was subsequently submitted to a total prophylactic gastrectomy. The surgical specimen only revealed foci of signet-ring cell carcinoma (SRCC) in situ without lymphoma signs. We highlight here the occurrence of other pathology in high-risk patients as well as its possible influence on the decision to perform gastrectomy.

A mutação do gene CDH1 determina um risco aumentado de desenvolvimento precoce de cancro gástrico de células em anel de sinete (tipo difuso). Apresentamos um caso de um doente jovem portador de uma mutação no gene CDH1 que foi diagnosticado com linfoma de MALT gástrico numa endoscopia de vigilância. O doente foi submetido a terapêutica de erradicação da Helicobacter pylori e subsequentemente realizou uma gastrectomia total profilática. A avaliação histológica da peça cirúrgica identificou focos de carcinoma in situ de células de anel em sinete, sem evidência de linfoma. O nosso objetivo é salientar a ocorrência de outras patologias em doentes de alto risco assim como a sua possível influência na decisão cirúrgica.

Breve historia y fisiopatología del covid-19 / A brief history and pathophysiology of covid-19

PROPÓSITO: este artículo se realizó para contribuir con la difusión del conocimiento sobre el COVID-19 en la lengua hispana. HALLAZGOS: el SARS-CoV-2 fue descubierto en diciembre del 2019 y se difundió mundialmente desde entonces; el 11 de marzo de 2020 la OMS declaró globalmente estado de pandemia. Mientras fue incrementando la gravedad y frecuencia del COVID-19 en el mundo, la comunidad científica trabajó arduamente produciendo evidencia capaz de dilucidar los detalles de esta patología. Esta serie de artículos pretende agregar información lo más actualizada posible, interpretándola y adaptándola a la realidad boliviana. SUMARIO: la elaboración de este artículo está basado en información conocida sobre la historia de la aparición de esta nueva enfermedad e información vigente y actualizada sobre las características fisiopatológicas descritas en la literatura mundial

RAD51Bme Levels as a Potential Predictive Biomarker for PD-1 Blockade Response in Non-Small Cell Lung Cancer.

Lung cancer (LC) cells frequently express high levels of programmed death-ligand 1 (PD-L1). Although these levels grossly correlate with the likelihood of response to specific checkpoint inhibitors, the response prediction is rather imperfect, and more accurate predictive biomarkers are mandatory. We examined the methylation profile of RAD51B (RAD51Bme) as a candidate predictive biomarker for anti-PD-1 therapy efficacy in non-small cell lung cancer (NSCLC), correlating with patients' outcome. PD-L1 immunoexpression and RAD51Bme levels were analysed in NSCLC samples obtained from patients not treated with anti-PD-1 (Untreated Cohort (#1)) and patients treated with PD-1 blockade (Treated Cohort (#2)). Of a total of 127 patients assessed, 58.3% depicted PD-L1 positivity (PD-L1+). RAD51Bme levels were significantly associated with PD-L1 immunoexpression. Patients with PD-1 blockade clinical benefit disclosed higher RAD51Bme levels (p = 0.0390) and significantly lower risk of disease progression (HR 0.37; 95% CI: 0.15-0.88; p = 0.025). Combining RAD51Bme+ with PD-L1+ improved the sensitivity of the test to predict immunotherapy response. PD-L1+ was also associated with lower risk of death (HR 0.35; 95% CI: 0.15-0.81; p = 0.014). Thus, RAD51Bme levels might be combined with validated predictive biomarker PD-L1 immunostaining to select patients who will most likely experience clinical benefit from PD-1 blockade. The predictive value of RAD51Bme should be confirmed in prospective studies.

Subtyping Lung Cancer Using DNA Methylation in Liquid Biopsies.

BACKGROUND: Lung cancer (LCa) is the most frequently diagnosed and lethal cancer worldwide. Histopathological subtyping, which has important therapeutic and prognostic implications, requires material collection through invasive procedures, which might be insufficient to enable definitive diagnosis. Aberrant DNA methylation is an early event in carcinogenesis, detectable in circulating cell-free DNA (ccfDNA). Herein, we aimed to assess methylation of selected genes in ccfDNA from LCa patients and determine its accuracy for tumor subtyping. METHODS: Methylation levels of APC, HOXA9, RARß2, and RASSF1A were assessed in three independent study groups (study group #1: 152 tissue samples; study group #2: 129 plasma samples; study group #3: 28 benign lesions of lung) using quantitative methylation-specific PCR. Associations between gene promoter methylation levels and LCa subtypes were evaluated using non-parametric tests. Receiver operating characteristic (ROC) curve analysis was performed. RESULTS: In study group #2, HOXA9 and RASSF1A displayed higher methylation levels in small-cell lung cancer (SCLC) than in non-small-cell lung cancer (NSCLC). HOXA9 displayed high sensitivity (63.8%), whereas RASSF1A disclosed high specificity (96.2%) for SCLC detection in ccfDNA. Furthermore, HOXA9 methylation levels showed to be higher in squamous cell carcinoma in comparison with adenocarcinoma in study group #1. CONCLUSIONS: Methylation level assessments in ccfDNA may provide a minimally invasive procedure for LCa subtyping, complementing standard diagnostic procedures.

A panel of four immunohistochemical markers (CK7, CK20, TTF-1, and p63) allows accurate diagnosis of primary and metastatic lung carcinoma on biopsy specimens.

Accurate classification of lung cancer, as well as the differentiation between primary and metastatic carcinoma to the lung, mostly performed on biopsy or fine needle aspiration specimens, is critical for decisions on therapy and for determining prognosis. The limited amount of biopsy material available for morphological assessment has stimulated attempts to improve diagnostic accuracy through the use of immunohistochemistry (IHC), but an optimal IHC diagnostic algorithm has not been firmly established. We evaluated, on a retrospective series of biopsy specimens, the performance of a four-antibody IHC panel for accurate subclassification of non-small cell lung carcinoma (NSCLC) and for identification of metastatic carcinoma. Tumor morphology was assessed and IHC for CK7, CK20, TTF-1, and p63 was performed according to a two-step algorithm. Matched resection specimens served as gold standard and were compared with the corresponding biopsy. Of 443 biopsy specimens studied, 325 were diagnosed as primary carcinoma of the lung, 198 (44.7 %) as adenocarcinoma, 9 (2 %) as possibly adenosquamous carcinoma, 127 (28.7 %) as squamous cell carcinoma, and 40 (9 %) as NSCLC not further classifiable. Ten cases (2.3 %) were classified as adenocarcinoma of unknown origin and 58 (13 %) as metastasis. Importantly, of the primary lung adenocarcinomas, 35 (17.7 %) had been considered on clinical grounds as a metastasis from a previously diagnosed primary tumor. Of the 55 cases submitted to surgical resection in 47 (85.5 %) the biopsy diagnosis was confirmed, revealing substantial agreement (κ value = 0.757). Our two-step approach allows for accurate subclassification of NSCLC and also to distinguish between primary lung adenocarcinoma and metastasis, notably of colorectal adenocarcinoma, with crucial implications for appropriate patient management.

A novel type of familial proximal axonal dystrophy: three cases and a review of the axonal dystrophies.

Three related infants of Roma ancestry, two of them siblings, showed hypotonia, predominantly axial, from birth, difficulty swallowing, myoclonic seizures, and respiratory difficulty. Dysmorphic features, principally micrognathia were present. EEGs showed focal epileptiform abnormalities. All three died in their 5th month from respiratory insufficiency complicated by pneumonia. Autopsy showed small brains without malformation. Microscopy revealed numerous axonal spheroids involving particularly the brain stem and spinal cord, with especial prominence in the middle cerebellar peduncle, the anterior part of the thalamic reticular nuclei, and the anterior horns and columns of the spinal cord. Spheroids that appeared to be on axons of lower motor neurons were especially large. No spheroids were seen in peripheral nerves; electron microscopy did not show spheroids in skin. By electron microscopy spheroids contained neurofilaments, sparse mitochondria, and electron dense granules. The material did not allow identification of microtubules. Closely packed vesicles excluded neurofilamanets from the center of many spheroids, especially in the middle cerebellar peduncle. Sprouting of axons from the surface of many spheroids was seen. This disease is distinct from the well described type of infantile neuroaxonal dystrophy (Seitelberger's disease) in view of the distribution of spheroids, presence of spheroids on proximal rather than distal parts of axons, sparing of the peripheral nerves, lack of staining for synuclein, presence of sprouting, and lack of membranous profiles in the spheroids. A review of reported types of axonal dystrophy has not shown identical cases.

High-Grade Breast Epithelioid Angiosarcoma Secondary to Radiotherapy Metastasizing to the Contralateral Lymph Node: Unusual Presentation and Potential Pitfall.

BACKGROUND: Breast angiosarcoma is a rare disease occurring as primary tumour or secondary to lymphoedema or radiotherapy. The more frequent use of breast-conserving therapy and radiotherapy for breast carcinoma explains the increasing diagnosis of these tumours. CASE REPORT: We report a case of a breast epithelioid angiosarcoma which metastasized to the contralateral axillary lymph node, occurring 4 years after breast-conserving therapy with axillary lymph node dissection and radiotherapy. The patient presented skin lesions and an axillary lump (clinically diagnosed as carcinoma relapse and lymph node metastasis). Fine-needle cytology on both lesions and a core needle biopsy of the axillary lump were carried out. Differential diagnosis included carcinoma, malignant melanoma, and angiosarcoma. Immunohistochemistry confirmed the diagnosis of angiosarcoma. CONCLUSIONS: Breast angiosarcoma is a challenge - clinically, radiologically and pathologically - and requires a high index of suspicion in susceptible patients.