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Hyalinizing spindle and epithelioid cell nevus (Spitz nevus) is an uncommon melanocytic lesion. The histologic features of this benign tumor can mimic those of certain benign (dermatofibroma and desmoplastic cellular [...]

We reviewed the clinical records and pathologic material of 176 adults with primary soft tissue sarcomas treated at Memorial Sloan-Kettering Cancer Center between 1950 and 1985. Seventy-two patients (41%) had low-grade sarcomas and 104 (59%) had high-grade sarcomas. All but 18 patients underwent some form of excision as initial therapy. Adjuvant radiotherapy and chemotherapy combined with surgical excision showed no significant effect. A significantly increased risk of treatment failure was associated with large tumor size, positive surgical margins, bone involvement, local recurrence, metastatic spread, and high histologic grade. Except for recurrence, the p value by univariate analysis in the log-rank test for comparison of survival according to these clinical and pathologic characteristics was p, Sarcoma, cancer of the soft tissue that tends to be vascular and usually highly invasive, is frequently encountered as a painless swelling. Sarcomas of the head and neck represent less than 10 percent of all sarcomas. They carry a low survival rate for adults, although promising results have been achieved for children with the use of multi-agent chemotherapy. A review of 176 adult patients with head and neck sarcoma was undertaken in an attempt to identify factors that might predict prognosis and identify patients at high risk for non-response to treatment. These patients were treated between 1950 and 1985, and the minimum follow-up was two years. The average age was 48. Low-grade sarcoma was found in 72 patients (41 percent) and 104 patients had high-grade sarcoma. Surgical excision was the initial therapy for most patients; 18 patients had inoperable cancer. No significant benefit was obtained by the addition of radiotherapy or chemotherapy to the treatment regimen. Treatment failure was associated with large tumor size, excised tissue margins showing cancer, cancer involving the bone, local recurrence of disease, metastasis (spread outside the original site), and high histologic (tissue study) grade. The overall survival after two years was 75 percent; after five years, was 55 percent; and after 10 years, 46 percent. Patients who had high-grade sarcoma had 10-year survival of less than 20 percent, and only five patients who had high-grade metastatic sarcoma have survived (range 2 to 7 years). The histologic grade of sarcomas was a significant factor influencing overall survival. (Consumer Summary produced by Reliance Medical Information, Inc.)

AbstractContext: New biomarkers are needed in acetaminophen (APAP) hepatotoxicity. Plasma argininosuccinate synthetase (ASS) is a promising candidate.Objective: Characterize ASS in APAP hepatotoxicity.Methods: ASS was measured in plasma from rodents and humans with APAP hepatotoxicity.Results: In mice, ASS increased before injury, peaked before alanine aminotransferase (ALT) and decreased rapidly. Fischer rats had a greater increase in ASS relative to ALT. Patients with abnormal liver test results had very high ASS compared to controls. ASS appeared to increase early in some patients, and declined rapidly in all.Conclusions: ASS may be a useful biomarker of acute cell death in APAP hepatotoxicity.

Mitochondria generate reactive oxygen and peroxynitrite and release endonucleases during acetaminophen (APAP) hepatotoxicity. Because mitochondrial translocation of Bax can initiate these events, we investigated the potential role of Bax in the pathophysiology of hepatic necrosis after 300 mg/kg APAP in fasted C57BL/6 mice. APAP overdose induced Bax translocation from the cytosol to the mitochondria as early as 1 h after APAP injection. At 6 h, there was extensive centrilobular nitrotyrosine staining (indicator for peroxynitrite formation) and nuclear DNA fragmentation. In addition, mitochondrial intermembrane proteins were released into the cytosol. Plasma alanine aminotransferase (ALT) activities of 5610 ± 600 U/l indicated extensive necrotic cell death. Conversely, Bax gene knockout (Bax–/–) mice had 80% lower ALT activities, less DNA fragmentation, and less intermembrane protein release at 6 h. However, immunohistochemical staining for nitrotyrosine or APAP protein adducts did not show differences between wild-type and Bax–/–mice. In contrast to the early hepatoprotection in Bax–/–mice, plasma ALT activities (7605 ± 480 U/l) and area of necrosis (53 ± 6% hepatocytes) in wild-type animals was similar to values in Bax–/–mice at 12 h. In addition, there was no difference in DNA fragmentation or nitrotyrosine immunostaining. We concluded that the rapid mitochondrial Bax translocation after APAP overdose has no effect on peroxynitrite formation but that it contributes to the mitochondrial release of proteins, which cause nuclear DNA fragmentation. However, the persistent oxidant stress and peroxynitrite formation in mitochondria may eventually trigger the permeability transition pore opening and release intermembrane proteins independently of Bax.

Posttransplant lymphoproliferative disorders (PTLDs) usually are of B-cell lineage and associated with Epstein-Barr virus (EBV). PTLDs of T-cell lineage are much less common and infrequently associated with EBV. We report a rare case of a girl in whom B-cell and T-cell PTLDs developed following 2 EBV-negative kidney transplants. Within 2 years of the second transplantation, the originally EBV-negative patient developed both an EBV-associated clonal B-cell PTLD involving lymph nodes and an EBV-positive T-cell PTLD involving bone marrow and liver. These proliferations occurred concurrently with evidence of primary EBV infection and high plasma viral load. The patient eventually died of multiorgan failure 5 years after the initial transplant (3 years after the second transplant). To our knowledge, only 4 cases of both B-cell and T-cell PTLDs have been reported. Only 2 cases have been proven to be monoclonal and EBV-associated, as in this case, the first following kidney transplantation.

Fine-needle aspiration (FNA) is used commonly for the diagnosis of pulmonary neoplasms. It has been reported that thyroid transcription factor-1 (TTF-1) is a sensitive and specific marker for certain primary lung tumors. To the authors' knowledge, the use of TTF-1 immunostaining on FNA smears has not been documented in the literature. This study was designed to examine the utility of TTF-1 immunostaining on FNA specimens from various types of lung tumors by comparing the expression rates on Papanicolaou (Pap)-stained and Diff-Quik (DQ)-stained smears with the expression rates on cell block (CB) sections. Forty-three FNA specimens of lung tumors were studied, including 34 primary tumors (14 adenocarcinomas, 12 squamous carcinomas, and 8 small cell carcinomas) and 9 metastatic tumors. One Pap-stained slide and one DQ-stained slide were selected from each tumor. The cytologic material from the slides was transferred to positively charged slides. Unstained recuts were obtained from the CB sections. All slides were stained with TTF-1 monoclonal antibody using heat-induced epitope retrieval and a labeled polymer detection system. Twelve of 14 pulmonary adenocarcinomas were positive for TTF-1 (11 specimens on both CB sections and Pap-stained smears and 1 specimen on all 3 preparations, including the DQ-stained smear). Two of 14 adenocarcinomas were negative for TTF-1. Of 12 pulmonary squamous carcinomas, only 1 was positive for TTF-1 (on the CB section and the Pap-stained smear); the others were negative in all 3 preparations. Of eight small cell lung carcinomas, six specimens showed positive staining for TTF-1 on both CB and Pap-stained preparations; one of those also was positive on the DQ-stained smear. The remaining two small cell lung carcinomas were negative for TTF-1 in all three preparations. All metastatic tumors were negative for TTF-1. TTF-1 immunostaining of pulmonary neoplasms was applicable to FNA smears that were stained previously with the Pap technique, and the rate of positive staining in each tumor type was identical to the rate of positive staining in CB sections and was comparable to that reported in previous publications. Smears previously stained with the DQ method were unreliable for TTF-1 immunostaining. Cancer (Cancer Cytopathol) 2004;102:000–000. © 2004 American Cancer Society.

Acetaminophen (AAP) overdose causes formation of nitrotyrosine, a footprint of peroxynitrite, in centrilobular hepatocytes. The importance of peroxynitrite for the pathophysiology, however, is unclear. C3Heb/FeJ mice were treated with 300 mg/kg AAP. To accelerate the restoration of hepatic glutathione (GSH) levels as potential endogenous scavengers of peroxynitrite, some groups of animals received 200 mg of GSH/kg i.v. at different time points after AAP. AAP induced severe liver cell damage at 6 h. Total liver and mitochondrial glutathione levels decreased by >90% at 1 h but recovered to 75 and 45%, respectively, of untreated values at 6 h after AAP. In addition, the hepatic and mitochondrial glutathione disulfide (GSSG) content was significantly increased over baseline, suggesting a mitochondrial oxidant stress. Moreover, centrilobular hepatocytes stained for nitrotyrosine. Treatment with GSH at t= 0 restored hepatic GSH levels and completely prevented the mitochondrial oxidant stress, peroxynitrite formation, and liver cell injury. In contrast, treatment at 1.5 and 2.25 h restored hepatic and mitochondrial GSH levels but did not prevent the increase in GSSG formation. Nitrotyrosine adduct formation and liver injury, however, was substantially reduced. GSH treatment at 3 h after AAP was ineffective. Similar results were obtained when these experiments were repeated with glutathione peroxidase-deficient animals. Our data suggest that early GSH treatment (t= 0) prevented cell injury by improving the detoxification of the reactive metabolite of AAP. Delayed GSH treatment enhanced hepatic GSH levels, which scavenged peroxynitrite in a spontaneous reaction. Thus, peroxynitrite is an important mediator of AAP-induced liver cell necrosis.

Clear cell carcinoma of the gynecologic tract has been defined in terms of its clinical and histologic features; however, its immunophenotypic profile has not been fully characterized. Seventeen cases of primary clear cell carcinoma from various sites within the female genital tract (11 ovary, 5 uterus, 1 vagina) were analyzed by immunohistochemistry. These tumors were assessed for the expression of cytokeratin 7 (CK7), cytokeratin 20 (CK20), low and high molecular weight cytokeratins (CAM5.2 and 34E12, respectively), carcinoembryonic antigen (CEA), Leu-M1, vimentin, estrogen receptor (ER), progesterone receptor (PR), bcl-2, p53, HER-2/neu, and CA-125. The characteristic immunoprofile for all sites was positivity for CK7, CAM5.2, 34E12, CEA, Leu-M1, vimentin, bcl-2, p53, and CA-125; variably positivity for ER and HER-2/neu; and negativity for CK20 and PR. For comparison, two cases of urologic clear cell carcinoma (1 bladder, 1 urethra) were also studied, and their profile was found to be similar to the gynecologic cases. Aside from minor differences, clear cell carcinoma appears to have the same immunophenotype regardless of whether it originates in the endometrium, ovary, or genitourinary tract. Much of its profile is similar to other gynecologic adenocarcinomas, but some of the markers studied may be useful in the differential diagnosis of this tumor.

Excessive apoptotic cell death is implicated in a growing number of acute and chronic disease states. Caspases are critical for the intracellular signaling pathway leading to apoptosis. The aim of this investigation was to evaluate the efficacy and the mechanism of action of the novel caspase inhibitor CV1013 in a well-characterized model of TNF-induced apoptosis. Administration of 700 mg/kg galactosamine/100 μg/kg endotoxin (Gal/ET) induced hepatocellular apoptosis in C3Heb/FeJ mice as indicated by increased caspase-3 activity (706% above controls) and enhanced DNA fragmentation (3400% above controls) at 6 h. In addition, apoptosis was aggravated by the neutrophil-induced injury at 7 h (ALT activities: 4220 ± 960 U/L and 48 ± 4% necrosis). All animals died 8–12 h after Gal/ET treatment from shock and liver failure. A dose of 10 or 1 mg/kg of CV1013 administered three times (3, 4.5, and 5.5 h after Gal/ET) effectively prevented caspase-3 activation and parenchymal cell apoptosis at 6 h as well as the subsequent neutrophil-induced aggravation of the injury at 7 h after Gal/ET treatment. Animals treated with 10 mg/kg CV1013 survived for 24 h without liver injury. CV1013 reduced the processing of caspase-3 and caspase-8. This suggests that CV1013 may have inhibited the small amount of active caspase-8 generated at the receptor level. Because of the multiple amplification loops used to activate the entire caspase cascade, blocking the initial intracellular signal by CV1013 was highly effective in preventing apoptotic cell death. CV1013 has therapeutic potential for disease states with excessive apoptosis.

The mechanism of liver cell injury induced by an overdose of the analgesic acetaminophen (AAP) remains controversial. Recently, it was hypothesized that a significant number of hepatocytes die by apoptosis. Since caspases have been implicated as critical signal and effector proteases in apoptosis, we investigated their potential role in the pathophysiology of AAP-induced liver injury. Male C3Heb/FeJ mice were fasted overnight and then treated with 500 mg/kg AAP. Liver injury became apparent at 4 h and was more severe at 6 h (plasma ALT activities: 4110 ± 320 U/liter; centrilobular necrosis). DNA fragmentation increased parallel to the increase of plasma ALT values. At 6 h there was a 420% increase of DNA fragmentation and a 74-fold increase of terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL)-positive cells located predominantly around central veins. However, the activity of the proapoptotic caspase-3 was not increased at any time after AAP. In contrast, injection of the anti-Fas antibody Jo-2 (positive control) caused a 28-fold increase of caspase-3 activity and severe DNA fragmentation before significant ALT release. Treatment with the caspase inhibitor ZVAD-CHF2had no effect on AAP toxicity but completely prevented Jo-mediated apoptosis. In contrast, Jo-induced caspase activation and apoptosis could be inhibited by AAP treatment in a time- and dose-dependent manner. We conclude that AAP-induced DNA fragmentation does not involve caspases, suggesting a direct activation of endonucleases through elevated Ca2+levels. In addition, electrophilic metabolites of AAP may inactivate caspases or their activation pathway. This indicates that AAP metabolism has the potential to inhibit signal transduction mechanisms of receptor-mediated apoptosis.

Antibodies against cellular adhesion molecules protect against neutrophil-induced hepatic injury during ischemia-reperfusion and endotoxemia. To test if p2integrins on neutrophils and intercellular adhesion molecule-1 (ICAM-1) on endothelial cells are involved in neutrophil sequestration in the hepatic vasculature, neutrophil accumulation in the liver was characterized during the early phase of endotoxemia. Intravenous injection of Salmonella enteritidis endotoxin induced a dose-dependent activation of complement, tumor necrosis factor-α (TNF-α) formation, and an increase of hepatic neutrophils with maximal numbers at 5 mg/kg (90 min: 339 ± 14 cells/50 high power fields; controls: 18 ± 2). Administration of 15 μg/kg TNF-α and intravascular complement activation with cobra venom factor (75 αg/kg) had additive effects on hepatic neutrophil accumulation compared with each mediator alone. Monoclonal antibodies (2 mg/kg) to ICAM-1 and the a-chain (CD11a, CD11 b) or the β-chain (CD18) of β2integrins had no significant effect on hepatic neutrophil count after endotoxin. In contrast, these antibodies inhibited peritoneal neutrophil infiltration in response to glycogen administration by 28 (CD11b), 60 (CD11a, ICAM-1), and 92 (CD18). Our data suggest that TNF-α and complement factors contribute to hepatic neutrophil sequestration during the early phase of endotoxemia. Despite the fact that these inflammatory mediators can up-regulate integrins and ICAM-1, these adhesion molecules are not necessary for neutrophil accumulation in hepatic sinusoids. The protective effect of these antibodies against neutrophil-induced liver injury appears to be due to inhibition of transendothelial migration and adherence to parenchymal cells.

The potential role of nitric oxide (NO) was investigated in the pathophysiology of liver injury after priming with 20 min hepatic ischemia-reperfusion and administration of .5 mg/kg Salmonella enteritidis endotoxin. Liver injury during the early reperfusion phase of 4 h was characterized by severe vascular oxidant stress, lipid peroxidation (LPO), neutrophil infiltration, and a 33 reduction of the microvascular blood flow in the liver. Inhibition of NO synthesis with N-nitro-L-arginine methyl ester hydrochloride (L-NAME) aggravated liver injury by 90, reduced LPO, and did not affect liver neutrophils but further impaired microvascular blood flow. Treatment with the NO-donor spermine-NONOate or L-arginine did not affect these parameters in postischemic animals, however, treatment did restore all values of L-NAME- treated animals back to disease control levels. These data suggest that endogenous NO formation is sufficient to limit ischemic liver injury during reperfusion but inhibition of NO synthesis will result in additional ischemic damage. NO may also be involved in scavenging of superoxide in the vasculature and in inducing LPO.

We studied the role of P‐selectin, an adhesion molecule known to be important for neutrophil localization to sites of inflammation, in a model of inflammatory liver injury. Male C3Heb/ FeJ (ET‐sensitive) mice treated with 700 mg/kg galactosamine and 100 μg/kg Salmonella abortus equiendotoxin (Gal/ET), murine tumor necrosis factor α (TNF‐α,15 μg/kg), or interleukin‐1 (IL‐1, 13–23 μg/kg), showed increased P‐selectin mRNA levels in the liver. In contrast, C3H/HeJ (ET‐resistant) mice responded only to cytokines with P‐selectin mRNA formation. Whereas no P‐selectin expression was detectable in control livers, there was temporary staining of endothelium in large blood vessels but not in sinusoids between 3 and 5 h after ET, TNF‐α, or IL‐1 treatment. Severe liver injury induced by Gal/ET at 7 h was not inhibited by an anti‐P‐selectin antibody in C3Heb/FeJ mice or in P‐selectin‐deficient animals. Sequestration of neutrophils in sinusoids, i.e. those neutrophils that have been identified as critical for the injury, was not affected by the antibody or in P‐selectin‐deficient mice. However, the temporary margination in portal and postsinusoidal venules was reduced by 75% in anti‐P‐selectin antibody‐treated animals and by 51% in P‐selectin‐deficient mice. We conclude that hepatic P‐selectin gene transcription in vivo involves cytokines. However, blocking P‐selectin neither attenuated sinusoidal neutrophil sequestration nor prevented neutrophil‐induced liver injury during endotoxin shock but attenuated neutrophil margination in larger vessels. Thus, our data demonstrate similarities and fundamental differences in the requirement for adhesion molecules to localize neutrophils in the liver vasculature compared to other organs during an inflammatory response. J. Leukoc. Biol. 63: 288–296; 1998.

The potential role of reactive oxygen species generated by Kupffer cells and neutrophils was investigated in a model of endotoxin-enhanced liver injury after hepatic ischemia. Male Fischer rats were subjected to 20 min ischemia and reperfusion of up to 24 h; .5 mgkg Salmonella enteritidisendotoxin was injected at 30 min of reperfusion. The animals developed severe liver injury resulting in 50 hepatocellular necrosis at 24 h. Isolated Kupffer cells and neutrophils from the postischemic liver generated 10-fold more superoxide than cells from control livers. Treatment with gadolinium chloride (GdCl3) selectively reduced the capacity of Kupffer cells to generate superoxide by 65 and attenuated liver injury by 73 at 4 h and 58–69 at 24 h. Monoclonal antibodies against neutrophil adhesion molecules (CD11CD18) had no effect on the early injury but reduced hepatocellular necrosis by 90–95 at 24 h. The antioxidant Trolox and the iron-chelator deferoxamine attenuated liver injury by 71 and 80, respectively. It is concluded that Kupffer cells are mainly responsible for the initial injury, and neutrophils are the dominant cytotoxic cell type during the later phase. Reactive oxygen generated by both cell types is critical for this pathogenesis.

The increased expression of Mac‐1 (CD11b/CD18) adhesion glycoproteins on neutrophils was studied using flow cytometry in male Fischer 344 rats treated with 5 mg/kg Salmonella cnteritidisendotoxin. A rapid and sustained threefold increase of Mac‐1 expression was observed after endotoxin injection. Inhibition of complement activation with the soluble complement receptor type 1 (sCRl) completely suppressed the initial up‐regulation of Mac‐1 (≤ 15 min) but did not prevent the activation during the later phase (30–90 min). During that time period, Mac‐1 expression increased in parallel with the concentration of tumor necrosis factor α (TNF‐α) in plasma and could be significantly attenuated with TNF antiserum. To verify the results, isolated human neutrophils were incubated with rat plasma obtained at various times after endotoxin injection. Using shape change as indicator of neutrophil activation, complement and TNF‐α could be identified as responsible mediators for neutrophil activation during endotoxemia in vivo. In contrast, the massive neutrophil accumulation in the liver after endotoxin was only slightly reduced by sCRl and unaffected by TNF antiserum. It is concluded that Mac‐1 up‐regulation on neutrophils after endotoxin injection in vivo may have limited relevance for hepatic neutrophil infiltration but may be important for the pathogenesis of endotoxin‐induced liver injury by facilitating adherence‐dependent neutrophil cytotoxicity. J. Leukoc. Biol.55: 105–111; 1994.

To determine the role of neutrophils in the pathogenesis of hepatic ischemia/reperfusion injury, livers from male Fischer rats were subjected to 45 min of no‐flow ischemia followed by reperfusion for up to 24 h. Two phases of liver injury were identified, an initial phase during the first hour of reperfusion and a later progression phase with 80 ± 3% hepatocyte necrosis and an 80‐fold increase of neutrophil infiltration in the liver after 24 h. Pretreatment with a monoclonal antibody against neutrophils, which caused consistent neutropenia, protected the liver from reperfusion injury as indicated by 28 ± 10% necrosis, and 84% reduction of hepatic neutrophil accumulation and a complete recovery of the hepatic ATP content. Our data suggest that the later progression phase of reperfusion injury after hepatic no‐flow ischemia is mediated mainly by neutrophils.—Jaeschke, H.; Farhood, A.; Smith, C. W. Neutrophils contribute to ischemia/reperfusion injury in rat liver in vivo. FASEB J.4: 3355–3359; 1990.

Collagenous spherulosis is an uncommon, usually incidental finding in breast tissue removed for a variety of reasons. A case of collegenous spherulosis, presenting as mammographic microcalcifications and diagnosed by stereotactic core needle biopsy, is used to address this relatively new diagnosis modality for the evaluation of non-palpable breast lesions. In this case, the microcalcifications were present exclusively within aollagenous spherulosis and no other abnormalities were obseved. With the increasing use of stereotactic core-needle biopsy it is important that pathologies become familier with this technique and its limitations, as well as the unusual lesions it may uncover.

The potential role of intercellular adhesion molecule‐1 (ICAM‐1) in the pathogenesis of reperfusion injury was investigated in male Fischer rats subjected to 45 min of hepatic ischemia and 24 h of reperfusion. ICAM‐1 mRNA levels increased during ischemia in the ischemic liver lobes; however, during reperfusion mRNA levels increased in both the ischemic and nonischemic lobes. Immunohistochemical evaluation indicated ICAM‐1 expression only on sinusoidal lining cells in controls; ischemia‐reperfusion enhanced ICAM‐1 expression in the sinusoids and induced some expression on hepatocytes. The monoclonal anti–ICAM‐1 antibody 1A29, but not an immunoglobulin G control antibody, administered at 1 h and 8 h of reperfusion (2 mg/kg) significantly attenuated liver injury as indicated by 51% lower plasma alanine aminotransferase activities and 32–36% less hepatic necrosis at 24 h without affecting reactive oxygen formation by Kupffer cells and hepatic neutrophils. Although 1A29 reduced neutrophil extravasation in a glycogen peritonitis by 60%, the antibody had no significant effect on hepatic neutrophil infiltration during reperfusion. These data suggest that ICAM‐1 plays a significant role during the neutrophil‐dependent injury phase after hepatic ischemia and reperfusion and therefore blocking this adhesion molecule may have therapeutic potential against postischemic acute liver failure. J. Leukoc. Biol. 57: 368–374; 1995.

In this report, we correlate the clinical and morphologic features of bilateral choroid plexus cysts in three fetuses. These cysts were detected as incidental findings during sonography at 18 to 20 weeks gestation before elective abortion. Two fetuses were normal; the third had trisomy 18. All cysts were present bilaterally in the posterior horns of the lateral ventricles and ranged from 0.5 cm to 1.0 cm in diameter. The walls were translucent, and the cavities were filled with clear serous fluid, except for the left cyst in the third fetus, which was hemorrhagic. The cysts were surrounded by the loose stroma of the choroid plexus. We believe that the formation of these cysts is related to the histogenesis of the choroid plexus. Although such cysts have now been described by sonographers in several fetuses with chromosomal anomalies, this association may reflect ascertainment bias. At this time, we therefore advise caution in interpreting sonographic evidence of isolated choroid plexus cysts as anomalous.

Liposarcomas of the larynx are very rare. A review of the English literature revealed only 28 published reports of tumours in this anatomical location. Diagnosis requires a high index of suspicion and careful histologic analysis. We present a case of a well-differentiated liposarcoma of the epiglottis, the tenth reported case at this laryngeal subsite. Initial biopsy specimens showed histological characteristics of a liposarcoma, which facilitated provision of optimal surgical treatment after careful analysis of published literature.