Malignant struma ovarii: a blinded study of 86 cases assessing which histologic features correlate with aggressive clinical behavior.

CONTEXT: Struma ovarii exhibiting malignant histology are uncommon, and an aggressive clinical course in the form of initial extraovarian spread or recurrence is even more exceptional for these tumors. OBJECTIVE: To determine whether specific histologic features have predictive value in distinguishing clinically benign from clinically malignant struma ovarii. DESIGN: Blinded analysis of 19 histologic characteristics of thyroid tumors was performed in 60 clinically benign and 26 clinically malignant struma ovarii cases, with long-term follow-up. RESULTS: Except for lack of fibrosis and macrofollicular pattern, which were more common in biologically malignant tumors (P  =  .04 and P  =  .008, respectively), and trabecular pattern, which was associated with a benign clinical course (P  =  .03), none of the other histologic features was found to be correlated with clinical behavior. The presence of the following features was similar in the biologically benign and malignant tumors: papillae, pseudo-papillae, psammoma bodies, nuclear grooves, nuclear overlap, "orphan Annie" nuclei, nuclear pseudo-inclusions, prominent nucleoli, hypercellularity, colloid scalloping, eosinophilic cytoplasm, mitoses, vascular invasion, cytologic atypia, nuclear pleomorphism, and cell size and type. Trabecular pattern and absence of fibrosis were uncommon, and there was considerable overlap of macrofollicular pattern ratio between benign and malignant cases. Thus, their practical usefulness is uncertain. CONCLUSIONS: The clinical outcome of struma ovarii cannot be predicted based on the microscopic diagnosis of the thyroid tissue or on specific histologic features. The lack of correlation between morphology and outcome in proliferative and histologically malignant struma ovarii is striking, making the behavior of these tumors particularly unpredictable.

Protection against chronic pancreatitis and pancreatic fibrosis in mice overexpressing pancreatic secretory trypsin inhibitor.

OBJECTIVES: Mutations in the gene encoding for pancreatic secretory trypsin inhibitor (PSTI) can contribute to chronic pancreatitis. In the current study, we tested whether overexpression of PSTI-I in mice protects against chronic pancreatitis and pancreatic fibrosis. METHODS: Rat PSTI-I expression was targeted to pancreatic acinar cells in transgenic mice. Chronic pancreatitis was achieved by intraperitoneal injection of cerulein for 10 weeks. Pancreatitis severity was assessed by histological grading of inflammatory infiltrate, atrophy, and fibrosis; quantitation of myeloperoxidase (MPO) activity; quantitative morphometric analysis of collagen content; and measurements of type I collagen, fibronectin, and transforming growth factor beta mRNA expression. RESULTS: Cerulein administration to nontransgenic mice produced histological evidence of inflammatory infiltrate, glandular atrophy, and parenchymal fibrosis and increased collagen production, MPO activity, and collagen I and fibronectin mRNA levels. In cerulein-treated PSTI transgenic mice, there were significant reductions in inflammatory infiltrate, MPO activity, fibrosis, and collagen I and fibronectin mRNA levels. Transgenic mice treated with cerulein had significantly less collagen than nontransgenic mice. CONCLUSIONS: The severity of chronic pancreatitis and pancreatic fibrosis is significantly reduced in mice expressing rat PSTI-I. We propose that pancreatic trypsin inhibitors play a protective role in the pancreatic response to repeated injurious events.

Malignant struma ovarii: an analysis of 88 cases, including 27 with extraovarian spread.

Struma ovarii that display extraovarian spread or later recurrence is exceedingly rare. Among 88 patients with "malignant" struma ovarii followed for prolonged periods, several features helped to predict the adverse clinical course. Adhesions (graded 2 to 4+), peritoneal fluid (> or =1 L) or ovarian serosal rent were worrisome features, occurring in 74% of 27 biologically malignant tumors but only 10% of 61 clinically benign tumors. The size of the strumal component rather than the overall size of the ovarian teratoma also had some predictive value. Tumors with a strumal component < or =6 cm recurred rarely (7%), whereas 33% of the consult and 88% of the literature cases > or =12 cm were clinically malignant. Except for a papillary pattern or poorly differentiated cancer, no microscopic feature reliably predicted the clinical outcome, including those typically associated with malignancy in primary thyroid tumors. Among the consult cases, 7% with histologic follicular adenomas and 29% with papillary carcinomas were clinically malignant. Unequivocal vascular invasion was rare, precluding assessment of its effect. Optically clear nuclei, when extensive, were useful to diagnose papillary carcinoma, but were present nevertheless in smaller numbers in both macrofollicular and microfollicular adenomas. Eight tumors confined initially to the ovary (stage 1) recurred. Papillary carcinomas recurred earlier (average 4 y) than follicular adenomatous neoplasms (average 11 y, range: 1-29 y). Overall, the survival rate for all patients was 89% at 10 years and 84% at 25 years, indicating the need for routine long-term follow-up.

Transgenic expression of pancreatic secretory trypsin inhibitor-I ameliorates secretagogue-induced pancreatitis in mice.

BACKGROUND & AIMS: Endogenous trypsin inhibitors are believed to inhibit protease activity if trypsin becomes inadvertently activated within the acinar cell. However, this action remains unproven, and the role of endogenous pancreatic trypsin inhibitors in acute pancreatitis is unknown. In this study, we tested whether increased levels of pancreatic secretory trypsin inhibitor-I (PSTI-I) in mice could prevent secretagogue-induced pancreatitis. METHODS: Rat PSTI-I expression was targeted to pancreatic acinar cells in transgenic mice by creating a minigene driven by the rat elastase I enhancer/promoter. Secretagogue-induced pancreatitis was achieved by 12 hourly intraperitoneal injections of caerulein. The severity of pancreatitis was assessed by measurements of serum amylase, histologic grading, and pancreas wet weight-to-body weight ratio. Trypsinogen activation and trypsin activity were measured in pancreatic extracts. RESULTS: Targeted expression of PSTI-I to the pancreas increased endogenous trypsin inhibitor capacity by 190% (P <.01) in transgenic vs. nontransgenic mice. Caerulein administration to nontransgenic mice produced histologic evidence of acute pancreatitis, and significantly elevated serum amylase and pancreas weight ratio. In caerulein-treated transgenic mice, the histologic severity of pancreatitis was significantly reduced. There was no difference in trypsinogen activation peptide levels between caerulein-treated transgenic and nontransgenic mice. However, trypsin activity was significantly lower in transgenic mice receiving caerulein compared with nontransgenic mice. CONCLUSIONS: These data demonstrate that the severity of secretagogue-induced pancreatitis is significantly ameliorated in mice with higher pancreatic levels of trypsin inhibitor. We propose that PSTI-I prevents pancreatitis by inhibiting the activity of trypsin, rather than by reducing trypsinogen activation.

Primary sensory neurons: a common final pathway for inflammation in experimental pancreatitis in rats.

We hypothesized that neurogenic inflammation is a common final pathway for parenchymal inflammation in pancreatitis and evaluated the role of primary sensory neurons in secretagogue-induced and obstructive pancreatitis. Neonatal rats received either the primary sensory neuron-denervating agent capsaicin (50 mg/kg s.c.) or vehicle. At 8 wk of age, pancreatitis was produced by six hourly injections of caerulein (50 microg/kg i.p.) or by common pancreaticobiliary duct ligation (CPBDL). The severity of pancreatitis was assessed by serum amylase, pancreatic myeloperoxidase (MPO) activity, histological grading, pancreatic plasma extravasation, and wet-to-dry weight ratio. Caerulein significantly increased MPO activity and wet-to-dry weight ratio, produced histological evidence of edematous pancreatitis, induced plasma extravasation, and caused hyperamylasemia. CPBDL increased MPO activity and produced histological evidence of pancreatitis. Neonatal capsaicin administration significantly reduced tissue MPO levels, histological severity scores, and wet-to-dry weight ratio and abolished plasma extravasation. These results demonstrate that primary sensory neurons play a significant role in the inflammatory cascade in experimental pancreatitis and appear to constitute a common final pathway for pancreatic parenchymal inflammation.