Artur Zembowicz

Pigmented epithelioid melanocytoma: A low-grade melanocytic tumor with metastatic potential indistinguishable from animal-type melanoma and epithelioid blue nevus

In the course of a study of borderline melanocytic tumors, we observed a distinctive group of lesions characterized by features very similar to those previously described in the literature as “animal-type melanoma” and epithelioid blue nevus of Carney complex. We have designated these lesions as pigmented epithelioid melanocytoma (PEM). Herein, we present a clinical-pathologic analysis of 41 consecutive PEM from 40 patients and compare them with 11 epithelioid blue nevi from patients with Carney complex. PEM occurred in both sexes of different ethnic backgrounds, including white, Hispanic, black, Asian, and Persian. The median age of occurrence was 27 years (range 0.6–78 years). Tumors had wide distribution with extremities being the most common site. The tumors were formed by deep dermal (mean Breslows thickness 3.3 mm) proliferation of heavily pigmented epithelioid and/or spindled melanocytes. Five lesions were part of combined nevus. Ulceration was present in 7 cases. Tumor necrosis was present in 1 case. Regional lymph nodes were sampled in 24 cases (59%). In 11 cases, lymph nodes contained metastases (46%). Liver metastases occurred in 1 case. None of the patients died of disease. Clinical follow-up of more than a year (mean 32 months, range up to 67 months) was available in 27 cases (67%). We found no histologic criteria separating metastasizing and nonmetastasizing PEM. Ulceration was the only feature more common in PEM than epithelioid blue nevi of Carney complex. Otherwise, they were histologically indistinguishable. Our data show that PEM is a unique low-grade variant of melanoma with frequent lymph node metastases but indolent clinical course. We suggest that PEM be considered as a provisional histologic entity encompassing both animal-type melanoma and epithelioid blue nevus.

Dermal dendritic melanocytic proliferations: an update.

Dermal dendritic melanocytic proliferations are a broad group of congenital and acquired melanocytic lesions characterized by the presence of dermal spindled and dendritic cells resembling melanocytes migrating from the neural crest to the epidermis. Historically, they were subdivided into dermal melanocytoses (naevus of Ota, Ito, Mongolian spot and related conditions), blue naevi and malignant blue naevi. The purpose of this review is to provide an update on recent developments in the field with emphasis on new entities and their differential diagnosis.

Involvement of nitric oxide in the endothelium‐dependent relaxation induced by hydrogen peroxide in the rabbit aorta

1 The effects of hydrogen peroxide (H2O2, 0.1–1 mm) on the tone of the rings of rabbit aorta precontracted with phenylephrine (0.2–0.3 μm) were studied. 2 H2O2 induced a concentration‐dependent relaxation of both the intact and endothelium‐denuded rings. However, in the presence of intact endothelium, H2O2‐induced responses were 2–3 fold larger than in its absence, demonstrating the existence of endothelium‐independent and endothelium‐dependent components of the vasorelaxant action of H2O2. 3 The endothelium‐dependent component of H2O2‐induced relaxation was prevented by NG‐nitro‐l‐arginine methyl ester (l‐NAME, 30 μm) or NG‐monomethyl‐l‐arginine (300 μm), inhibitors of nitric oxide synthase (NOS), in a manner that was reversible by l‐, but not by d‐arginine (2 mm). The inhibitors of NOS did not affect the responses of denuded rings. 4 Methylene blue (10 μm), an inhibitor of soluble guanylate cyclase, blocked H2O2‐induced relaxation of both the intact and denuded rings. 5 H2O2 (1 mm) enhanced the efflux of cyclic GMP from both the endothelium‐intact and denuded rings. The effect of H2O2 was 4 fold greater in the presence of intact endothelium and this endothelium‐dependent component was abolished after the inhibition of NOS by l‐NAME (30 μm). 6 In contrast to the effects of H2O2, the vasorelaxant action of stable organic peroxides, tert‐butyl hydroperoxide or cumene hydroperoxide, did not have an endothelium‐dependent component. Moreover, they did not potentiate the efflux of cyclic GMP from the rings of rabbit aorta. 7 Exogenous donors of NO, specifically, 3‐morpholinosydnonimine (SIN‐1), glyceryl trinitrate or sodium nitroprusside were used to decrease the tone of denuded rings to the level induced by endogenous NO released from intact endothelium. This procedure did not influence the vasorelaxant activity of H2O2, showing that H2O2 does not potentiate the vasorelaxant action of NO within the smooth muscle. 8 Thus, H2O2‐induced relaxation in the rabbit aorta has both endothelium‐dependent and independent components. The endothelium‐dependent component of the relaxant action of H2O2 is due to enhanced endothelial synthesis of NO.

Whole-Slide Imaging Digital Pathology as a Platform for Teleconsultation: A Pilot Study Using Paired Subspecialist Correlations

CONTEXT -Whole-slide imaging technology offers promise for rapid, Internet-based telepathology consultations between institutions. Before implementation, technical issues, pathologist adaptability, and morphologic pitfalls must be well characterized. OBJECTIVE -To determine whether interpretation of whole-slide images differed from glass-slide interpretation in difficult surgical pathology cases. DESIGN -Diagnostically challenging pathology slides from a variety of anatomic sites from an outside laboratory were scanned into whole digital format. Digital and glass slides were independently diagnosed by 2 subspecialty pathologists. Reference, digital, and glass-slide interpretations were compared. Operator comments on technical issues were gathered. RESULTS -Fifty-three case pairs were analyzed. There was agreement among digital, glass, and reference diagnoses in 45 cases (85%) and between digital and glass diagnoses in 48 (91%) cases. There were 5 digital cases (9%) discordant with both reference and glass diagnoses. Further review of each of these cases indicated an incorrect digital whole-slide interpretation. Neoplastic cases showed better correlation (93%) than did cases of nonneoplastic disease (88%). Comments on discordant cases related to digital whole technology focused on issues such as fine resolution and navigating ability at high magnification. CONCLUSIONS -Overall concordance between digital whole-slide and standard glass-slide interpretations was good at 91%. Adjustments in technology, case selection, and technology familiarization should improve performance, making digital whole-slide review feasible for broader telepathology subspecialty consultation applications.

Roles of IL-1 and TNF in the decreased ileal muscle contractility induced by lipopolysaccharide

Gastrointestinal stasis during sepsis may be associated with gastrointestinal smooth muscle dysfunction. Endotoxin [lipopolysaccharide (LPS)] impairs smooth muscle contraction, in part through inducible nitric oxide synthase (NOS II) and enhanced nitric oxide production. We studied the roles of tumor necrosis factor-α (TNF) and interleukin-1 (IL-1) in this process by using TNF binding protein (TNFbp) and IL-1 receptor antagonist (IL-1ra). Rats were treated with TNFbp and IL-1ra, or their vehicles, 1 h before receiving LPS or saline. At 5 h after LPS, contractility was measured in strips of ileal longitudinal smooth muscle, and NOS II activity was measured in full-thickness segments of ileum. LPS decreased maximum stress (mean ± SE) from 508 ± 55 (control) to 355 ± 33 g/cm2( P < 0.05). Pretreatment with TNFbp plus IL-1ra prevented the LPS-induced decrease. Separate studies of TNFbp alone or IL-1ra alone indicated that, at the doses and timing used, TNFbp was more effective. LPS also increased NOS II activity by >10-fold ( P < 0.01) over control. This increase was prevented by TNFbp plus IL-1ra ( P = not significant vs. control). We conclude that the LPS-induced increase in NOS II activity and the decrease in ileal muscle contractility are mediated by TNF and IL-1.Gastrointestinal stasis during sepsis may be associated with gastrointestinal smooth muscle dysfunction. Endotoxin [lipopolysaccharide (LPS)] impairs smooth muscle contraction, in part through inducible nitric oxide synthase (NOS II) and enhanced nitric oxide production. We studied the roles of tumor necrosis factor-alpha (TNF) and interleukin-1 (IL-1) in this process by using TNF binding protein (TNFbp) and IL-1 receptor antagonist (IL-1ra). Rats were treated with TNFbp and IL-1ra, or their vehicles, 1 h before receiving LPS or saline. At 5 h after LPS, contractility was measured in strips of ileal longitudinal smooth muscle, and NOS II activity was measured in full-thickness segments of ileum. LPS decreased maximum stress (mean +/- SE) from 508 +/- 55 (control) to 355 +/- 33 g/cm2 (P < 0.05). Pretreatment with TNFbp plus IL-1ra prevented the LPS-induced decrease. Separate studies of TNFbp alone or IL-1ra alone indicated that, at the doses and timing used, TNFbp was more effective. LPS also increased NOS II activity by >10-fold (P < 0.01) over control. This increase was prevented by TNFbp plus IL-1ra (P = not significant vs. control). We conclude that the LPS-induced increase in NOS II activity and the decrease in ileal muscle contractility are mediated by TNF and IL-1.

Morphological analysis of nevoid melanoma: a study of 20 cases with a review of the literature.

Nevoid melanoma is a rare variant of melanoma characterized by deceptive morphologic features reminiscent of a benign melanocytic nevus. Twenty (13 nodular, 7 verrucous) nevoid melanomas were reviewed with the goal of identifying the predominant architectural patterns, cytologic features, and prognostic indicators. Although at scanning magnification, many lesions showed a strong resemblance to banal compound or dermal nevi, careful inspection in all cases demonstrated subtle pleomorphism and impaired maturation with depth, invariably accompanied by multiple dermal mitoses. Four tumors recurred and three metastasized, with subsequent death of the patients. Follow-up information for a period of at least 3 years was available in eight cases. In this group, mortality was 37.5%, the metastasis rate was 37.5%, and the local recurrence rate was 75%, with an average tumor thickness of 2.5 mm. We conclude that nevoid melanoma may be distinguished from a benign melanocytic nevus by a high index of suspicion, a careful analysis of architecture, and attention to cytologic features. Our data and a review of the literature do not support the notion that nevoid melanoma has a better prognosis than ordinary melanoma.

Transcriptional Regulation of Endothelial Nitric-oxide Synthase by Lysophosphatidylcholine

We have shown that lysophosphatidylcholine (lyso-PC) increases endothelial nitric-oxide synthase (eNOS) expression at the transcriptional level (Zembowicz, A., Tang, J.-L., and Wu, K. K. (1995) J. Biol. Chem. 270, 17006–17010). To elucidate the mechanism by which lyso-PC increases the eNOS transcription, we identified Sp1 sites at −104 to −90 and PEA3 sites at −40 to −24 as being involved in lyso-PC-induced promoter activity. Site-directed mutagenesis of Sp1 sites resulted in a marked reduction of basal and lyso-PC-induced activity whereas PEA3 site mutation abrogated response to lyso-PC. Band shift assays revealed that lyso-PC augmented Sp1 binding activity. Pretreatment of cells or nuclear extracts with okadaic acid reduced the Sp1 binding activity. Furthermore, okadaic acid treatment abrogated the lyso-PC induced promoter augmentation. Lyso-PC increased the nuclear extract protein phosphatase 2A (PP2A) activity, which was suppressed by okadaic acid treatment. These results suggest that lyso-PC up-regulates eNOS transcription by a PP2A-dependent increase in Sp1 binding activity.

Warfarin-induced skin necrosis

Warfarin-induced skin necrosis is a rare complication of anticoagulant therapy with a high associated morbidity and mortality requiring immediate drug cessation. Cutaneous findings include petechiae that progress to ecchymoses and hemorrhagic bullae. Characteristic dermatopathological findings are diffuse dermal microthrombi with endothelial cell damage and red cell extravasation with progression to full-thickness coagulative necrosis. The lesions of warfarin-induced skin necrosis may be difficult to differentiate from mimickers, but skin biopsy in conjunction with careful consideration of the clinical history, including time of onset, cutaneous distribution of the lesions, and laboratory findings, are essential for prompt diagnosis and patient treatment. Herein, we review the clinical and histologic features helpful for differentiating warfarin-induced skin necrosis and report a case illustrative of the diagnostic difficulty that may at times be encountered in clinical practice.

Induction of cyclooxygenase-2 in human umbilical vein endothelial cells by lysophosphatidylcholine.

Lysophosphatidylcholine (lysoPC), a component of atherogenic lipoproteins and atherosclerotic lesions, has been recently suggested to play a role in atherogenesis. LysoPC is known to induce several endothelial genes involved in leukocyte recruitment, mitogenesis, and inflammation. Cyclooxygenases (prostaglandin H2 synthases) are rate-limiting enzymes involved in the endothelial synthesis of prostacyclin, an antiplatelet, vasorelaxant, and vasoprotective molecule. We investigated the effect of lysoPC on the endothelial expression of cyclooxygenases. Our results demonstrate that, in cultured human umbilical vein endothelial cells, lysoPC induces cyclooxygenase-2 mRNA and protein levels. Increased expression of cyclooxygenase-2 is accompanied by the enhancement of both basal- and calcium ionophore A23187-induced synthesis of prostacyclin. Nuclear runoff experiments demonstrated an increased rate of transcription of the cyclooxygenase-2 gene by lysoPC. In contrast, lysoPC did not affect the expression of constitutive cyclooxygenase-1. Our results suggest that the induction of endothelial cyclooxygenase-2 by lysoPC may be an important vasoprotective mechanism that limits progression of atherosclerotic lesions and promotes their regression.

CD20+ T-cell lymphoma: clinicopathologic analysis of 9 cases and a review of the literature.

Rare cases of CD20+ T-cell lymphoma (TCL) have been reported, but the clinicopathologic spectrum of this disorder is not known. We identified 9 cases of CD20+ TCL diagnosed at our institution and 26 additional cases through a search of the English language literature. Among current cases, there were 7 men (ages 71 to 81, median 75 y) and 2 women (ages 36 and 37 y). Five patients presented with predominantly nodal disease (localized in 3 and widespread in 2 cases) and 4 patients presented with purely extranodal disease involving the parotid glands, skin, or small intestine. CD20 was uniformly and strongly expressed in 5 cases and dimly expressed or present on a subset of neoplastic cells in 4 cases. The proportion of CD20+ T cells changed over time in 3 cases. Three cases fulfilled diagnostic criteria for clinicopathologically defined subtypes of TCL (2 mycosis fungoides; 1 enteropathy-type TCL), whereas 6 were peripheral TCL unspecified with variable cytomorphology, T-cell immunophenotype, and sites of involvement. In 8 of 9 cases, a clonal T-cell population was identified by molecular genetic analysis. Among 8 cases with clinical follow-up, 5 behaved aggressively with death from disease within 3 years of diagnosis in 4 cases (median survival: 11 mo, range: 1 to 35 mo), and recurrent disease at 10 months in 1 case; 1 patient died of an EBV+ B-cell lymphoma (BCL) 66 months after the original diagnosis; in the remaining 2 cases, patients were alive and undergoing treatment (follow-up: 4 and 18 mo). Historical cases showed similar clinicopathologic variability. CD20+ TCL is rare, and clinically and pathologically heterogeneous. When CD20 expression is present in TCL, it may be dimmer than that of normal B cells, suggesting neoplastic transformation of a normal CD20dim+ T-cell subset. Cases of CD20+ TCL in which the proportion of CD20+ cells changes over time may reflect aberrant expression of CD20, possibly as an activation marker, by neoplastic T cells. CD20+ TCL may cause diagnostic difficulty, particularly in cases that clinically and pathologically mimic BCL. Knowledge of the unusual phenomenon of CD20 expression in TCL, in conjunction with careful morphologic analysis, the use of a panel of antibodies, and molecular genetic studies, is important in avoiding a misdiagnosis of BCL.