The clinicopathologic spectrum and genomic landscape of de-/trans-differentiated melanoma.

Dedifferentiation and transdifferentiation are rare and only poorly understood phenomena in cutaneous melanoma. To study this disease more comprehensively we have retrieved 11 primary cutaneous melanomas from our pathology archives showing biphasic features characterized by a conventional melanoma and additional areas of de-/trans-differentiation as defined by a lack of immunohistochemical expression of all conventional melanocytic markers (S-100 protein, SOX10, Melan-A, and HMB-45). The clinical, histologic, and immunohistochemical findings were recorded and follow-up was obtained. The patients were mostly elderly (median: 81 years; range: 42-86 years) without significant gender predilection, and the sun-exposed skin of the head and neck area was most commonly affected. The tumors were deeply invasive with a mean depth of 7 mm (range: 4-80 mm). The dedifferentiated component showed atypical fibroxanthoma-like features in the majority of cases (7), while additional rhabdomyosarcomatous and epithelial transdifferentiation was noted histologically and/or immunohistochemically in two tumors each. The background conventional melanoma component was of desmoplastic (4), superficial spreading (3), nodular (2), lentigo maligna (1), or spindle cell (1) types. For the seven patients with available follow-up data (median follow-up period of 25 months; range: 8-36 months), two died from their disease, and three developed metastases. Next-generation sequencing of the cohort revealed somatic mutations of established melanoma drivers including mainly NF1 mutations (5) in the conventional component, which was also detected in the corresponding de-/trans-differentiated component. In summary, the diagnosis of primary cutaneous de-/trans-differentiated melanoma is challenging and depends on the morphologic identification of conventional melanoma. Molecular analysis is diagnostically helpful as the mutated gene profile is shared between the conventional and de-/trans-differentiated components. Importantly, de-/trans-differentiation does not appear to confer a more aggressive behavior.

Her-2/neu assessment for gastric carcinoma: validation of scoring system.

BACKGROUND/AIMS: Gastric cancer is the second leading cause of cancer mortality in the world. Amplification of HER-2/neu oncogene has become an important biomarker for identifying patients who respond to HER-2 targeting therapy. A number of studies have analyzed HER-2/neu overexpression in gastric carcinoma, and the rate of HER2 positivity is variable, ranging from 6% to 35%. METHODOLOGY: In our study HER-2/neu expression was assessed on 73 samples of primary gastric cancer, using immunohistochemistry. For 19 patients preoperative biopsy samples and resected specimens were available. Additionally, internal ring study was performed to estimate intraobserver variability of IHC scoring among pathologists at our department. RESULTS: HER-2/neu overexpression was found in 10 (13.6%) of the tested samples, and it was more common in intestinal (22.5%) than the diffuse type (3.7%). Not one of the 6 analyzed mixed type tumors showed HER-2/neu expression. For the paired samples (preoperative biopsy samples and resected specimens) the concordance rate for HER-2/neu expression was 94.7%. CONCLUSIONS: According to high concordance rate in paired samples we consider it appropriate to evaluate HER2 expression on biopsy specimens, especially in unresectable cases, and to re-evaluate it on resected specimens if available, due to high heterogeneity of a gastric cancer.

An unusual cause of the ileus: non-specific stenosing ulceration of the small intestine.

Non-specific ulcerations of the small intestine are very rare. The cause and pathogenesis of these lesions remain obscure. The diagnosis of primary ileal ulcer is commonly overlooked and infrequently is established intraoperatively. Here we described a case of a 73-year-old woman who was presented to the emergency surgical department with the five days history of vomiting, distension, constipation, and abdominal pain. On physical examination abdomen was mildly distended and diffusely painful on palpation. Bowel sounds were present and active. Plain abdominal x-ray film showed ileus of the small intestine. Multislice computed tomography showed stenosing process of the ileum. Patient underwent exploratory laparotomy. Approximately 60 cm from the ileocecal valve ileum was inflamed and hypertrophic with a point of obstruction. Grossly, it appeared as a small intestine carcinoma. Involved segment of ileum including the point of obstruction was resected. Pathological examination showed ulceration of the ileum. After the surgery the patient made rapid recovery and was discharged from the hospital on the tenth postoperative day.

Apoptosis, proliferation and Fas ligand expression in placental trophoblast from pregnancies complicated by HELLP syndrome or pre-eclampsia.

OBJECTIVE: To investigate apoptosis, proliferation and Fas ligand expression of placental trophoblast in the hemolysis, elevated liver enzymes, low platelets (HELLP) syndrome and in pre-eclampsia (PE), and to compare this with normal pregnancies. DESIGN: Prospective study. SETTING: University hospital in Croatia. SAMPLE: Placentae from women with HELLP syndrome (n=10), PE (n=10) and normal pregnancies (n=10). METHODS: The HELLP syndrome was diagnosed with platelets <100×10(9) /L, aspartate aminotransferase (AST) and alanine transaminase (ALT) >70 U/L and lactic acid dehydrogenase (LDH) > 600 U/L. Pre-eclampsia was diagnosed at blood pressure >140/90 mmHg, with proteinuria >300 mg/L/24 hours. For detection of apoptosis and proliferation in villous trophoblast, antibodies M30 and Ki-67 were used. Expression of Fas ligand was assessed using immunohistochemistry and the semiquantitative HSCORE method. MAIN OUTCOME MEASURES: Apoptosis, proliferation and Fas ligand expression in villous trophoblast. RESULTS: Apoptosis, proliferation and Fas ligand expression were higher in villous trophoblast in HELLP syndrome than in the PE group (p=0.015, p=0.018 and p=0.002, respectively) and the control group (p=0.000, p=0.012 and p=0.049, respectively). Placentae from the PE group had higher levels of apoptosis (p=0.019), lower Fas ligand expression (p=0.029) and no difference in proliferation (p=0.887) compared with the control group. CONCLUSIONS: There is an increase in apoptosis, proliferation and Fas ligand expression in placentae from women with HELLP syndrome compared with placentae from PE and normal pregnancies. Our findings indicate the possibility of differential mechanisms behind HELLP syndrome and PE.

Angiomyomatous hamartoma of the popliteal lymph nodes in a patient with Klippel-Trenaunay syndrome: case report.

We present a case of angiomyomatous hamartoma (AMH) in the popliteal region of a patient with Klippel-Trenaunay syndrome. A 14-year-old boy with a right popliteal mass and recurrent edema of the right leg was admitted to a local hospital where a diagnosis of Klippel-Trenaunay syndrome was made. Three lymph nodes in the right popliteal fossa were removed. Histopathologic examination showed angiomyomatous hamartomas. Postoperatively, the patient was followed for 6 years. He had occasional mild edema of the right leg, but no signs of inflammation or recurrence of the angiomyomas. Our case is the first reported case of angiomyomatous hamartoma in a patient with Klippel-Trenaunay (KT) syndrome.

Acute respiratory failure on a low dose of amiodarone - is it an underdiagnosed and undertreated condition?

Amiodarone-induced pulmonary toxicity (AIPT) has a variety of presentations. Amiodarone use has been rarely associated with the development of acute respiratory failure. We present a patient with a history of paroxysmal atrial fibrillation who developed acute respiratory distress syndrome despite taking a low dose of amiodarone and having no risk or precipitating factors. The diagnosis of AIPT was made after drug discontinuation and exclusion of other potential causes. The development of acute respiratory failure due to AIPT is often underdiagnosed and undertreated. Better identification of risk factors and developing appropriate diagnostic tools for risk stratification of patients receiving amiodarone is mandatory.

Expression of EGF, EGFR, and proliferation in placentas from pregnancies complicated with preeclampsia.

OBJECTIVE: To investigate proliferation, EGF and EGFR expression of villous trophoblast (VTB), decidual cells (DC), and extravillous trophoblast (EVTB) in the placentas from pregnancies complicated with preeclampsia (PE) and to compare them with placentas from normal pregnancies. METHODS: Twenty-nine PE placentas and 19 control placentas were studied for EGF and EGFR immunohistochemical expression (noted as week, moderate or strong). Proliferation was expressed as the proliferation index. The CK7 antibody was used to distinguish DC from EVTB. RESULTS: DC and EVTB proliferation was significantly higher in PE placentas. EGFR and EGF expression showed no significant difference. CONCLUSION: Higher DC and EVTB proliferation in PE could contribute to PE development.

Immunohistochemical expression of RECK protein in placental membranes of the preterm delivery with and without chorioamnionitis.

OBJECTIVE: To compare the immunohistochemical expression of RECK protein in placental membranes of late preterm delivery in women with and without histologically proven chorioamnionitis. STUDY DESIGN: Fetal membranes were collected from women who had late preterm delivery with (n=8) and without (n=9) histologic chorioamnionitis. Immunohistochemistry for RECK protein was performed on formalin fixed and paraffin-embedded sections. The two groups were matched for age, body mass index and parity. SPSS Version 13.0 was used for statistical analysis. RESULTS: There was weaker immunohistochemical expression of RECK protein in placental membranes of women with histologic chorioamnionitis compared to control subjects (P=0.0498). CONCLUSIONS: Chorioamnionitis has an impact on immunohistochemical expression of RECK protein in placental membranes in late preterm delivery.

Expression of inflammatory cytokines in placentas from pregnancies complicated with preeclampsia and HELLP syndrome.

OBJECTIVE: To investigate the expression of tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6) and interleukin-10 (IL-10) in villous trophoblast, syncytial knots and decidua placentas from pregnancies complicated with preeclampsia (PE), Hemolysis, Elevated Liver enzymes and Low Platelet count (HELLP) syndrome and gestational age-matched controls. METHODS: Study group included 35 placentas from pregnancies complicated with PE and 35 placentas from pregnancies with HELLP syndrome. Control group included 35 placentas from idiopathic preterm labor. Placentas were matched according to the gestational age. Expression of TNF-α, IL-6 and IL-10 was determined by immunohistochemistry and semi-quantitative HSCORE method in villous trophoblast, syncytial knots and decidua. Non-parametric statistics were used for analyses. RESULTS: There was no difference in the expression of TNF-α, IL-6 and IL-10 in all the studied placental segments between PE, HELLP and gestational age-matched control group. TNF-α (F = 32, 41, p < 0.001), IL-6 (F = 58, 53, p < 0.001) and IL-10 (F = 17, 62, p < 0.001) expression was significantly different in different placental cell types, the highest expression of cytokines was in decidua. CONCLUSION: There was no difference in cytokine expression in villous trophoblast, syncytial knots and decidua among the studied placental groups. The expression of cytokines was highest in decidua in all the studied placental groups.

Trophoblast apoptosis in human term placentas from pregnancies complicated with idiopathic intrauterine growth retardation.

OBJECTIVE: To investigate proliferative, apoptotic, and antiapoptotic activity of placental trophoblast in pregnancies complicated with idiopathic intrauterine growth retardation (IUGR). METHODS: Study group included data and placentas from 52 normal singleton term pregnancies with idiopathic IUGR. Records and placentas from 69 singleton pregnancies with normal fetal growth served as a control group. IUGR was defined by birth weight less than 10th percentile of standard values. Children with congenital malformations and those born with the signs of hypoxia, laboratory or clinical signs of preeclampsia or infection, children born to anemic mothers and those born from pregnancies with an increased coagulation system activity were excluded. RESULTS: There was no statistically significant difference in the cytotrophoblast proliferation index value (Z = 0.24; P = 0.553), trophoblast expression of the Bcl-2 antiapoptotic factor (Z = 0.47; P = 0.634), and trophoblast apoptotic index (Z = 0.51; P = 0.613) between the idiopathic IUGR and control group. CONCLUSION: The proliferative and apoptotic events in the trophoblast of placentas with idiopathic IUGR did not differ from physiologic ones. Study results suggest the IUGR syndrome to have no uniform etiology or even underlying pathophysiology that would determine the possible fetal risk and subsequent long-term consequences for fetal health and life. This imposes the need of a more precise definition and unambiguous distinction between the idiopathic and other forms of IUGR.

Morphological characteristics of placentas associated with idiopathic intrauterine growth retardation: a clinicopathologic study.

OBJECTIVES: To investigate histopathologic findings, placental diameters and characteristics of syncytial knots in the placentas from idiopathic intrauterine growth retardation (IUGR) pregnancies, and to compare them with a normal birth weight group. STUDY DESIGN: Based on strict eligibility criteria, this prospective case-control study included 52 term placentas from idiopathic IUGR pregnancies and 69 term placentas from normal birth weight pregnancies. The study was carried out at the Clinical Hospital Centre, Split, where all placentas were collected and examined. For each placenta, diameters were measured and the following histopathologic findings were recorded: infarction, intervillous thrombosis, abruption, villous branching and maturation, chorioamnionitis, decidual vasculopathy and hemorrhagic endovasculitis for each placenta. In addition we assessed quantitative (number of syncytial knots and number of syncytial nuclei per syncytial knot) and qualitative (density and surface area) characteristics of syncytial knots in each placental sample. Statistical significance was tested using chi(2)-test, Student's t-test and Mann-Whitney U-test. Statistical significance was set at P< or =0.05. RESULTS: There was no difference in investigated histopathologic findings between idiopathic IUGR placentas and control group placentas. Placental diameters correlated significantly with neonatal birth weight (r=0.64; P<0.01); with higher birth weight there is an increase in placental diameters. Syncytial knots from idiopathic IUGR had significantly smaller surface area (Z=2.637; P=0.008) and higher density (Z=3.225; P=0.001) compared with the control group, while there is no difference in number of syncytial knots per individual villus, total number of syncytial knots in each placenta sample or number of syncytial nuclei per syncytial knot. CONCLUSIONS: The investigated histopathologic findings in idiopathic IUGR placentas are incidental, with no higher frequency than in placentas from uncomplicated pregnancies, and should not be considered as possible causative factors for idiopathic IUGR. The demonstrated qualitative changes of syncytial knots in placentas associated with IUGR could represent a compensatory mechanism.