Predicting the biologic behavior of ductal carcinoma in situ: an analysis of molecular markers.

BACKGROUND: Ductal carcinoma in situ (DCIS) of the breast encompasses a heterogeneous group of noninvasive cancers that now represents 19% of new breast cancer cases. Optimal treatment remains controversial. We undertook this study to characterize the relationship between angiogenic markers and the biologic behavior of various DCIS phenotypes. METHODS: We performed histopathologic review and immunohistochemistry for p53, vascular endothelial growth factor (VEGF), and factor VIII-related antigen on 103 specimens of pure DCIS. RESULTS: VEGF expression was seen in 89 tumors (86%) and correlated with microvessel density (MVD). Among VEGF-negative tumors, mean MVD (number of microvessels per square millimeter) was 48 +/- 19, versus 117 +/- 7 for tumors expressing VEGF (P =.001). Strong p53 expression was observed in 28 tumors (27%) and was associated with comedo histology, high tumor grade, necrosis, high MVD, and ipsilateral tumor recurrence (all P < or =.03). Among 8 patients with ipsilateral recurrence, 5 (63%) had tumors with strong p53 expression, whereas only 24% of patients without recurrence had tumors with strong p53 expression (P =.03). Although 7 of 8 patients with ipsilateral recurrence had tumors with VEGF and high MVD, neither parameter achieved statistical significance. CONCLUSIONS: These data suggest that molecular alterations may help predict the biologic aggressiveness of DCIS. Mutant p53 expression predisposes the patient toward ipsilateral recurrence, perhaps by promoting angiogenesis. Further investigation may identify clinically useful markers and novel treatment strategies.

Effect of image compression on telepathology. A randomized clinical trial.

CONTEXT: For practitioners deploying store-and-forward telepathology systems, optimization methods such as image compression need to be studied. OBJECTIVE: To determine if Joint Photographic Expert Group (JPG or JPEG) compression, a glossy image compression algorithm, negatively affects the accuracy of diagnosis in telepathology. DESIGN: Double-blind, randomized, controlled trial. SETTING: University-based pathology departments. PARTICIPANTS: Resident and staff pathologists at the University of Illinois, Chicago, and University of Cincinnati, Cincinnati, Ohio. INTERVENTION: Compression of raw images using the JPEG algorithm. MAIN OUTCOME MEASURES: Image acceptability, accuracy of diagnosis, confidence level of pathologist, image quality. RESULTS: There was no statistically significant difference in the diagnostic accuracy between noncompressed (bit map) and compressed (JPG) images. There were also no differences in the acceptability, confidence level, and perception of image quality. Additionally, rater experience did not significantly correlate with degree of accuracy. CONCLUSIONS: For providers practicing telepathology, JPG image compression does not negatively affect the accuracy and confidence level of diagnosis. The acceptability and quality of images were also not affected.

Micropthalmia transcription factor: a new prognostic marker in intermediate-thickness cutaneous malignant melanoma.

Micropthalmia transcription factor (Mitf) is involved in melanocyte development and differentiation. The current study was undertaken to determine whether there is a relationship between Mitf expression and survival in patients with intermediate-thickness (1.0-4.0 mm) melanoma. Original paraffin blocks or slides of the primary tumor were accessible in 63 such patients. Mitf expression was evaluated by immunocytochemistry and analyzed visually. Slides were graded as follows according to the percentage of cells whose nuclei stained positive for Mitf: (a) 0, 0%; (b) +1, 1-25%; (c) +2, 26-50%; (d) +3, 51-75%; and (e) +4, > 75%. Median follow-up was 50 months. Mean thickness was 2.2 +/- 0.7 mm. Mean overall survival was 171.90 +/- 13.12 months. Mean disease-free survival was 168.53 +/- 13.96 months. Fifty-two melanomas (82.5%) stained positive for Mitf. By univariate analysis, mean overall survival and disease-free survival in patients whose melanomas did not express Mitf were 80.89 +/- 17.98 months (median, 51 months) and 71.36 +/- 19.87 months (median, 40 months), respectively. This compares with 187.90 +/- 13.41 months (median, not reached) and 186.78 +/- 13.84 months (median, not reached), respectively, for patients whose melanomas expressed Mitf (P = 0.0086 and P = 0.0054). These findings persisted in multivariate analysis. In addition, patients with > 50% Mitf expression had significantly fewer nodal metastases after node dissection than patients with < or = 50% Mitf expression (P = 0.04). Our data suggest that Mitf may be a new molecular prognostic marker in patients with intermediate-thickness melanoma.

Pancreatic heterotopia and other uncommon causes of non-malignant biliary obstruction.

The vast majority of patients developing obstructive jaundice will have an underlying malignancy. When the etiology of the obstruction cannot be defined prior to operative intervention, identification of a non-malignant process will occur only subsequent to a major operation. The clinical course of a patient with complete distal common bile duct obstruction as the result of pancreatic heterotopia is discussed. This uncommon diagnosis prompted a review of the literature on this subject enabling this detailed discussion inclusive of the embryology, prevalence and clinical presentations of this entity. Our review further identified a varied group of other non-malignant causes of biliary obstruction that may be mistakenly interpreted to represent biliary or pancreatic malignancy.

Molecular prognostic markers in intermediate-thickness cutaneous malignant melanoma.

BACKGROUND: The limitations of morphologic criteria alone in determining the prognosis for a patient with a particular intermediate-thickness primary melanoma have prompted efforts to identify other markers. METHODS: In this study, the authors analyzed expression of p53, beta1 integrin, and beta3 integrin in primary tumors from 111 patients with intermediate-thickness malignant melanoma. RESULTS: Eighty-nine (80%) had detectable p53 protein, 58 (52%) expressed beta1 integrin, and 71 (64%) expressed beta3 integrin. Patients with beta3 positive melanomas were more likely to die of their disease (32 of 71 patients, 45%) than those with beta3 negative tumors (3 of 40 patients, 8%) (P < 0.0001). The number of involved lymph nodes, Clark's level, beta1 integrin expression, thickness, and mitotic rate also had prognostic significance. beta3 integrin was associated with subsequent lung metastases and beta1 integrin with lymph node involvement. CONCLUSIONS: Integrin expression, along with histopathologic criteria, is a prognostic marker for intermediate-thickness malignant melanoma and may indicate the site of subsequent metastasis. These observations may have clinical utility and suggest areas for future investigation.

Histological response to stent graft therapy.

BACKGROUND: The purpose of the present study was to examine the histological consequences of the endoluminal exclusion of blood flow effected with stent graft technology. METHODS AND RESULTS: In 25-kg mongrel dogs, patulous vein patch infrarenal aortoplasty with iliac vein produces a fusiform abdominal aortic dilation (AAD). All aortic tributaries were preserved. Endoluminal exclusion via transfemoral placement of a thin-wall Dacron graft occurred 4 +/- 2 months later (n = 23). Balloon-expandable stents anchored the ends of the graft to the aorta. Hematoxylin and eosin, elastin van Gieson's, and Masson's trichrome staining was performed 6 and 12 months later at death. In control nongrafted AADs, the arterial portion of the AAD was lined by elastin -and collagen-rich intimal hyperplasia, and the venous portion developed medial hyperplasia containing collagen but little elastin. After stent graft placement, the stent struts and the graft were completely incorporated into an elastin-poor, collagen-rich neointima. Fibrosis of the vein patch was observed at 1 year. laminated thrombus did not form in the AAD until immediately after stent graft placement; flow arrest occurred in the space between the graft and the AAD intima despite the patent tributaries. At 6 and 12 months, microscopic recanalization was seen in this thrombus, although macroscopic flow was not discernible by duplex imaging or angiography. No AAD growth was measured. CONCLUSIONS: Aortic dilation was not observed at 1 year after stent graft placement within AADs with patent side branches despite microscopic evidence of thrombus recanalization. A collagen-rich and elastin-poor neointima incorporated the entire stent graft.

Beta 1 integrin expression: a marker of lymphatic metastases in cutaneous malignant melanoma.

BACKGROUND: Experimental evidence suggests that integrins are key regulators of the development of melanoma metastases, influencing both the likelihood and site of metastases. Whereas effective treatment of cutaneous melanoma remains surgical, elective lymph node dissection (ELND) is controversial. The present study was designed to investigate the relationship between integrin expression by a given primary melanoma and occult regional lymph node metastases. MATERIALS AND METHODS: We studied beta 1 integrin expression, by quantitative immunohistochemistry using an image analyzer, in the primary melanomas of 90 ELND patients. RESULTS: beta 1 integrin was expressed in > or = 10% of the primary tumor in 92% of cases eith lymph node involvement versus 9% of node negative cases (p < 0.001). CONCLUSIONS: Our data demonstrate that quantitative immunohistochemistry for beta 1 integrin expression in primary melanomas can identify patients likely to have occult lymph node metastases. This suggests that beta 1 integrins play a role in the lymphatic dissemination of cutaneous melanoma.

Beta3 integrin expression in melanoma predicts subsequent metastasis.

Previous studies have suggested that differential expression and/or activation of integrins facilitates metastatic progression in murine and human melanoma. While recent data show that the integrin alphavbeta3 is involved in tumor angiogenesis and that tumor growth may be abrogated by alphavbeta3 inhibitors in vitro, the clinical significance of beta3 integrin expression in human malignant melanoma is not known. To assess the prognostic value of beta3 integrin expression, we examined primary cutaneous melanomas from 160 patients followed for a mean of 98 months or until death. We quantified the percentage of tumor area stained with beta3 integrin Ab CD-61 using an image analyzer. beta3 integrin expression was detected in 107/160 primary melanomas (69%). beta3-integrin-positive (beta3+) tumors were thicker (mean 2.98 +/- 0.3 mm) than beta3-integrin-negative (beta3-) melanomas (mean 1.64 +/- 0.2 mm) (P = 0.002). Patients with beta3+ melanomas were more likely to relapse (57/107, 53%) and to die from disease (45/107, 42%) than those with beta3- tumors (6/53, 11%; and 4/53, 8%, respectively) (P < 0.001). Overall survival was greater for beta3- than for beta3+ patients (mean 102 +/- 9 vs 69 +/- 6 months) (P = 0.001). These data show that beta3 integrin expression in primary cutaneous melanoma predicts subsequent metastatic progression. Further study of beta3 integrins in the development of melanoma metastases may yield new therapeutic strategies, as well as prognostic information, for the treatment of this cancer.

Beta 1 integrin expression in malignant melanoma predicts occult lymph node metastases.

BACKGROUND: Elective lymph node dissection for malignant melanoma is still controversial. Experimental studies suggest that differential expression, activation, or both of beta1 integrins facilitate melanoma metastases. However, the clinical significance of beta1 integrin expression in human melanoma is unclear. METHODS: We examined primary cutaneous melanomas from 76 patients undergoing elective lymph mode dissection. We quantified the percentage of tumor area stained by beta1 integrin antibody with an image analyzer. RESULTS: beta1 integrin was expressed in all 23 primary tumors from patients with pathologically positive lymph nodes (LNs) but in only 14 (26%) of 53 cases with pathologically negative nodes (p < 0.001). No patients with beta1 integrin-negative tumors had LN involvement, whereas 23 (62%) of 37 patients with beta1 integrin-positive tumors had LN metastases (p < 0.001). Furthermore, 21 (91%) of 23 cases with LN metastases but only 4 (8%) of 53 cases without had beta1 integrin staining of 10% or more of tumor area (p < 0.001). CONCLUSIONS: Our study is the first to show a correlation between expression of a molecular marker in the primary cutaneous melanoma and likelihood of regional LN metastases. beta1 immunostaining of 10% or more of tumor area reliably predicts patients most likely to harbor occult LN metastases and likely to benefit from ELND.

Prognostic significance of nucleolar organizer regions (NORS) in malignant melanoma.

Nucleolar organizer regions (NORs) are loops of ribosomal DNA (rDNA) in the nucleolus and are associated with acidic proteins. They are seen in routinely processed paraffin sections by using a one-step colloidal silver (Ag) staining method; they appear as black dots termed "AgNORs". The quantitative assay of AgNORs has been used to differentiate benign from malignant neoplasms. Melanocytic lesions differ significantly in AgNOR counts between malignant melanoma and nevi. However, conflicting results have been reported as to AgNORs' prognostic value in melanoma. A recent study showed AgNOR counts to be a more accurate prognostic indicator than Breslow's thickness. In this study, we counted the AgNORs in 26 patients with primary cutaneous melanomas (CMM) between 2.0 mm and 2.5 mm thick. Of these, 14 are alive without disease (AN) at 5 years after diagnosis (group 1) and 12 are dead of disease (DD) in less than 5 years (group 2). The AgNORs were scored in 30 nuclei per tumor, and the means were calculated. For group 1, the mean number of AgNORs per nucleus was 6.88, ranging from 3.73 to 12.70. For group 2, the mean number was 6.97, ranging from 3.63 to 11.67. Statistical analysis using analysis of variance (ANOVA) showed no significant difference between the groups (p = 0.33). In our study, AgNOR counts did not prove to be of prognostic value in malignant melanoma.

Spindle cell pseudotumors in the lungs due to Mycobacterium tuberculosis in a transplant patient.

A rare spindle cell pseudotumor in the skin, lymph nodes, and bone marrow has been previously reported in immunosuppressed transplant patients and patients with acquired immunodeficiency syndrome. All reported cases were caused by Mycobacterium avium-intracellulare or other nontuberculous mycobacteria. We are reporting spindle cell pseudotumors in the lungs caused by Mycobacterium tuberculosis. The patient had insulin-dependent diabetes mellitus and was status post cadaveric renal and pancreatic transplants. His hospital course was complicated by pulmonary tuberculosis due to M. tuberculosis. At autopsy, the lungs showed numerous bilateral gray nodules ranging from 0.2 to 2.5 cm. Microscopic examination uncovered a cellular proliferation composed of spindle cells arranged in fascicles. There were no granulomata. An acid-fast stain showed numerous acid-fast bacilli within the spindle cells. To our knowledge, this is the first case of spindle cell pseudotumor caused by M. tuberculosis of the lungs. Awareness of this unusual manifestation of mycobacterial infection in immunosuppressed patients underscores the need for acid-fast staining of biopsies with spindle cell proliferation even in the absence of overt granulomatous lesions in order to prevent misdiagnosis.

Clinical and pathologic findings in 2 siblings with congenital nephrotic syndrome.

We report the clinical and pathologic findings of 2 siblings affected with congenital nephrotic syndrome (CNS). The parents were a nonconsanguineous Mexican couple. The first sibling was born at term and developed proteinuria, hypoproteinemia, edema and ascites by its second month of life; he died septic at 6 months of age. The second sibling was diagnosed with congenital nephrosis during the second trimester of pregnancy. Prenatal demonstration of reno-placentomegaly can help in making the presumptive diagnosis of CNS in patients with high maternal serum and amniotic fluid AFP, normal acetylcholinesterase and normal karyotype. The pathologic findings of the kidneys of these siblings demonstrate that tubular microcysts are not critical to the disease process and are only the manifestation of a progressive disease in which the primary renal defect probably resides in a lack of integrity of the glomerular epithelial cells serving as filter.

Lipoid proteinosis: case report.

A 20-month-old Kuwaiti girl had manifestations of lipoid proteinosis, a rare autosomal recessive disorder seen more commonly in Caucasians. This condition is diagnosed based on clinical, histopathologic, and ultrastructural criteria. Its biochemical and genetic aspects are still poorly understood.