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Malignant peripheral nerve sheath tumors (MPNSTs) are diagnostically challenging neoplasms for which sensitive and specific immunohistochemical markers are lacking. Although limited to date, previous studies have suggested that NF1 (17q), NF2 (22q), p16 (9p), and EGFR (7p) alterations may be involved in MPNST tumorigenesis. To determine whether specific genetic changes differentiate between MPNST and morphologically similar neoplasms, we assessed these chromosomal regions in 22 MPNSTs (9 NF1-associated, 13 sporadic), 13 plexiform neurofibromas, 5 cellular schwannomas, 8 synovial sarcomas, 6 fibrosarcomas, and 13 hemangiopericytomas by 2-color FISH. NF1 deletions, often in the form of monosomy 17, were found in MPNSTs (76%). neurofibromas (31%), hemangiopericytomas (17%), and fibrosarcomas (17%), but not in synovial sarcomas or cellular schwannomas. NF1 losses were encountered more frequently in MPNSTs versus other sarcomas (p < 0.001), as were p16 homozygous deletions (45% vs 0%; p < 0.001), EGFR amplifications (26% vs 0%; p = 0.006), and polysomies for either chromosomes 7 (53% vs 12%; p = 0.003) or 22 (50% vs 4%; p < 0.001). Hemizygous or homozygous p16 deletions were detected in 75% of MPNSTs, but not in benign nerve sheath tumors (p < 0.001). Thus, FISH analysis identifies relatively specific genetic patterns that may be useful in selected cases, for which the differential diagnosis includes low- or high-grade MPNST.

Differentiating desmoplastic small round cell tumor (DSRCT) from another similar small round cell tumor of childhood, the Ewing sarcoma/primitive neuroectodermal tumor (EWS/PNET), can be difficult because morphologic and immunohistochemical features overlap. We studied the predictive value of immunohistochemistry with an antibody to the C-terminal region of the Wilms tumor (WT1) protein for differentiating DSRCT from EWS/PNET in 24 malignant small round cell tumors that had been previously diagnosed as DSRCT or EWS/PNET by standard methods. We performed reverse transcriptase-polymerase chain reaction (RT-PCR) analysis in cases with available tissue as a confirmatory measure: 6 of 13 DSRCTs were informative by RT-PCR, and 6 of 6 showed an EWS-WT1 fusion; all 13 DSRCTs showed strong, definitive nuclear staining with the WT1 antibody. All 11 EWS/PNETs were WT1 antibody negative; 7 of 11 cases classified as EWS/PNET were informative by RT-PCR, and 7 of 7 showed an EWS-FLI-1 fusion. For cases in which the morphologic and immunohistochemical features are consistent with a diagnosis of DSRCT, WT1 antibody staining predicts the EWS-WT1 translocation with high sensitivity and specificity and is, therefore, useful for differentiating DSRCT from EWS/PNET when genetic information is unavailable.

Our objective was to determine if placental histologic acute inflammation is related to maternal and fetal serum cytokine levels in preterm labor, using a data set previously constructed blinded to histopathologic information. To this goal in 1992, 32 consecutive patients at 20-36 weeks with progressive labor and tocolytic failure were recruited. Maternal serum sampled during the active phase of labor, and fetal (umbilical vein) serum were assayed by ELISA for levels of soluble interleukin-1 beta (IL-1 beta), soluble interleukin-2 receptor (IL-2 R), and interleukin 6 (IL-6) (T-Cell Diagnostics). Acute placental inflammation was scored by two groups blinded to clinical data, and the average scores analyzed for relationships to serum cytokine levels. Weighted kappa values, reflecting interobserver agreement in scoring of acute inflammation, were: amnion 0.84; choriodecidua 0.84; umbilical cord 0.85; and chorionic plate 0.73. Fetal levels of IL-1 beta and IL-2 R were higher with grade 3-4 acute amnionitis than with grades 0-2 (p = 0.022 and p = 0.023). Fetal levels of all three cytokines were higher in grade 3-4 umbilical vasculitis (IL-1 beta p = 0.008, IL-2 R p = 0.01, and IL-6 p = 0.03). In contrast, maternal serum cytokine levels were not associated with presence or severity of histologic evidence of acute placental inflammation. Histologic acute inflammation was not related to duration of labor, interval from membrane rupture to delivery, and presence or duration of antibiotic therapy. We conclude that fetal serum, but not maternal serum cytokine levels, are correlated with histologic evidence of acute placental inflammation, and may reflect a predominant placental origin of the cytokines.

Fine-needle aspirates of three thyroid nodules displayed hypercellularity and papillary tissue fragments that suggested neoplasms. Neither microfollicles (either empty or with inspissated colloid) nor the characteristic nuclei of papillary carcinoma were evident. Surgical specimens contained adenomatoid nodules with focal papillary hyperplasia. These cases demonstrate that no single cytologic feature should be used independently in the cytologic diagnosis of thyroid lesions. Tumor cellularity and papillary tissue fragments should not be equated with neoplasia per se; all cytomorphologic features should be evaluated.

Primitive neuroectodermal tumor (PNET), the second most common type of sarcoma in the first two decades of life, rarely presents as an organ-based neoplasm. Rather, it is seen typically in the soft tissues of the chest wall and paraspinal region. We report a case of primary PNET of the kidney in a 17-year-old girl who presented with abdominal pain, hematuria, and an abdominal mass. Nodules and sheets of monotonous-appearing primitive round cells and the formation of rosettes focally were the principal microscopic features. The tumor cells were uniformly immunoreactive for vimentin, cytokeratin, neuron-specific enolase, and 013 (CD99). In addition, the characteristic translocation of PNET and Ewing sarcoma, t(11;22)(q24;q12), was detected by polymerase chain reaction (PCR). Eight previous examples of renal PNET have been reported in the literature in the past 2 years, but only three of these cases have had complete immunohistochemical evaluation with the demonstration of 013 positivity. To our knowledge the present case is the only one to date demonstrating the recurrent translocation t(11;22)(q24;q12) by PCR. Assuming that the previous cases in the literature are bona fide examples of PNET, the kidney may be another site of predilection for this usual soft-tissue neoplasm. We are once again confronted with the dilemma about the nature of the progenitor cell.

Palpable thyroid nodules are common in women. The thyroid gland may enlarge in response to hyperemia, relative iodine depletion, and slight stimulation by beta Human Chorionic Gonadotrophin (HCG) during pregnancy. The presence of goiter or a discrete nodule requires investigation. Fine-needle aspiration (FNA), a reliable diagnostic tool, can be safely used during pregnancy. The tenet that a "histologic hyperplasia" accompanies the physiologic hyperplasia of pregnancy may hamper FNA interpretation. We reviewed 97 (10 previous, 46 pregnant, 13 postpartum, 1 spontaneous abortion, and 27 follow-up) aspirates of thyroid nodules from 57 patients. Cytologic diagnoses were divided into five categories: 31 benign, 7 cellular adenomatoid nodules, 5 suspicious for papillary carcinoma, 12 papillary carcinomas, and 2 follicular neoplasms. There were an unanticipated number of carcinomas. Lesions present before pregnancy did not show "progression" or significant change. No characteristic features ascribable to pregnancy were identified. Standard diagnostic criteria may be used in the evaluation of FNA of thyroid nodules from pregnant patients.

Angiogenesis is an important prognostic factor in infiltrating ductal carcinoma (IDC). Vascular endothelial growth factor (VEGF) stimulates angiogenesis in vivo. VEGF expression has been correlated with high vascularity in IDC. However, little is known about the prognostic significance of microvessel density (MVD) and its correlation with the expression of VEGF in infiltrating lobular carcinoma (ILC). We analyzed tumor samples from 51 patients with primary classic ILC to determine the relationship between tumoral MVD and VEGF expression. Cases of pleomorphic lobular carcinoma and tubulolobular carcinoma were excluded. Five-micron thick sections obtained from formalin-fixed, paraffin-embedded tissue blocks were immunostained with antibodies to factor VIII-related antigen (Dako, Carpenteria, CA) and VEGF (Calbiochem, Boston, MA). The former was used for MVD analysis. The vessel counts from the three most vascular fields (x200 magnification) were recorded and the highest of the vessel counts of the three fields was designated as the MVD. The intensity of VEGF staining and the proportion of cells staining were scored. Both the vessel counts and the scoring of VEGF staining were evaluated by two independent pathologists. The Student's t-test and Wilcoxon rank sum test were used to compare mean MVD and VEGF scores according to various clinical and pathologic features. All significance tests were two-sided with an alpha-level of 0.05. There was good correlation between the MVD of each observer (correlation coefficient 0.775, p < 0.001). There was no correlation of MVD or VEGF score with the size or stage of the tumor. In addition, the MVD or VEGF score was not significantly different between axillary lymph node-positive cases and node-negative cases, between patients with recurrence and those without, and between patients who survived and those who died of disease. There was, however, a weak negative correlation between the MVD and VEGF expression (Spearman correlation coefficient -0.08). Neither MVD or VEGF immunoscore were associated with tumor recurrence or vital status in patients with ILC. The absence of a statistically significant positive correlation between MVD and VEGF expression suggests that other factors may play a more important role in the angiogenesis of ILC.

Triton tumors are rare variants of malignant peripheral nerve sheath tumor (MPNST) with muscle differentiation, often seen in patients with neurofibromatosis 1 (NF1). Individuals affected with NF1 harbor mutations in the NF1 tumor suppressor gene and develop neurofibromas and MPNSTs. The NF1 gene is expressed in Schwann cells and its expression is lost in schwannian neoplasms, suggesting a role in malignant development. Separately, there is evidence that p53 suppressor gene mutations are involved in MPNSTs. To determine the role of the NF1 and p53 genes in the development of the malignant Triton tumor we examined 2 such tumors, 1 from a 3-year-old boy without clinical manifestations of NF1 and another from a 24-year-old man with NF1. Histological analysis of these tumors showed both neural and muscle differentiation with S-100 and desmin immunoreactivity, respectively. Reverse transcribed RNA polymerase chain reaction (RT-PCR) of NF1 mRNA showed NF1 expression in the sporadic tumor. Strong nuclear immunoreactivity for p53 was observed throughout the malignant population in both tumors. This was confirmed by loss of heterozygosity for p53 in the non-NF1 patient, suggesting that p53 is involved in both hereditary and sporadic Triton tumors. The finding of preserved NF1 gene expression in the non-NF1-related Triton tumor suggests that different genetic events predispose to the development of this rare neoplasm in sporadic cases.

Malignant peripheral nerve sheath tumors (MPNSTs) are uncommon soft tissue tumors. In children with neurofibromatosis 1 (NF1), a MPNST often arises in a preexisting neurofibroma, or may represent an initial manifestation without other obvious stigmata of the disease. The development of MPNSTs may be associated with instability of the p53 tumor suppressor gene since it is the most frequent genetic abnormality in soft tissue sarcomas. To assess the presence of p53 accumulation in MPNSTs and its correlation with clinical and pathologic features, we studied 12 neurofibromas (NFs), including 4 tumors with cellular features (one congenital) and 10 MPNSTs. Six MPNSTs were associated with NF1, all of which developed within a plexiform neurofibroma. Cell proliferation evaluated with an antibody to Ki-67 and nuclear p53 staining were both detected by immunohistochemistry We found p53 positivity in 60% of MPNSTs. All NFs except the congenital tumor were p53 immunonegative ( P < 0.01). Rare p53-positive nuclei were detected in the transitional zone in two of six MPNSTs arising in plexiform NFs. Ki-67 distinguished the NFs from MPNSTs ( P < 0.005). Half of the NF1 patients with p53-positive MPNSTs developed recurrence or metastases or developed a second malignancy within 2 years of diagnosis, whereas patients with p53-positive sporadic MPNSTs were free of disease 1 to 7 years later. We found p53 accumulation more frequently in NF1-associated MPNSTs. p53 mutations may be an additional biologic factor to account for the poor prognosis in these tumors.

Extramedullary hematopoiesis (EMH) usually accompanies a chronic hematologic disease in adults or prematurity in neonates. We observed a striking case of EMH in the explanted heart of a 13-year-old boy who underwent transplantation after extensive myocardial infarction. The florid myeloid proliferation raised the possibility of a leukemic process. To our knowledge, extensive myocardial EMH subsequent to myocardial infarction has not been previously reported. Possible mechanisms underlying EMH in the myocardium are presented.