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and Affiliated Clinics & Surgicenters, and Silver Cross Hospital (New Lennox, Illinois)

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Thromboembolism: More common than we think!


     The incidence of thromboembolism in the general population is not known, but it is estimated that the cumulative probability for confirmed thromboembolism ranges from 0.5% before age 50, to almost 11% by age of 80.  However, many events are not clinically recognized, which has led some authors to believe that the true cumulative incidence is about 28%.

     Risk factors for a thromboembolitic event are many: prolonged immobility, due to a leg fracture, a long car or airplane trip, or paralysis; varicose veins; obesity, with decreased physical activity; cardiac diseases, like congestive heart failure, or atrial fibrillation; increased estrogen, due to oral contraception, estrogen replacement, Tamoxifen, or pregnancy; autoimmune diseases, like Systemic Lupus Erythematosus; and cancer, typically colonic, ovarian, or multiple myeloma.  Still, many cases appear without a clear etiologic factor.  These cases are most likely associated with congenital abnormalities of coagulation factors, specifically Factor II and Factor V Leiden.

     Testing for the presence of mutation of these factors is now available.

     The Factor V Leiden gene mutation is the most common genetic risk factor for thrombosis and accounts for 90% of cases with activated protein C (APC) resistance. This mutation is involved in 20-40% of venous thrombosis cases and is present in 5% of the general population. Inherited thrombosis due to APC resistance is considered an autosomal dominant disease. Heterozygous carriers of the Factor 5 Leiden polymorphism have an increased risk of thrombosis of 5 to 10 times the general population. Homozygotes have a 50 to 100 fold increased risk of thrombosis. The presence of this mutation in pregnant women is also associated with higher risk for adverse pregnancy outcomes. Estimated penetrance for homozygotes is close to 80% with a reduced penetrance for heterozygotes (approximately 12 to 20%).

     Some indications for Factor V Leiden gene mutation are venous thrombosis, pulmonary embolism, transient ischemic attack or premature stroke, peripheral vascular disease, particularly lower extremity occlusive disease, cerebral vein thrombosis, multiple spontaneous abortions, history of a thrombotic event, family history of venous thrombosis, relative known to have factor V Leiden, presence of another known genetic hypercoagulability in an individual with a history of thrombosis, and prior to major surgery, pregnancy, oral contraceptive use, or estrogen therapy, if there is a personal or family history of thrombosis.

     The Factor II (20210A) gene mutation is also a common risk factor for thrombosis and is associated with elevated factor II (Prothrombin) levels in the peripheral blood. It is present in 1-3% of the general population and after the factor V Leiden mutation, it is the most common genetic risk factor for venous thrombosis. Higher concentrations of prothrombin lead to increased rates of thrombin generation, resulting in excessive growth of fibrin clots. It is an autosomal dominant disorder, with heterozygotes being at a 3 to 11 fold increased risk of thrombosis. Although homozygosity is rare, inheritance of two G20210A alleles would increase the risk of developing thrombosis further. If a patient is doubly heterozygous for both the Factor II (G20210A) Mutation and the Factor V Leiden (G1691A) Mutation, the combined heterozygosity leads to an earlier onset of thrombosis and tends to be more severe than single gene heterozygosity.

     Some indications for Factor II gene mutation testing are venous thrombosis, pulmonary embolism, premature myocardial infarction in women, premature ischemic stroke in the absence of hypertension, diabetes or hypercholesterolemia, cerebral vein thrombosis, history of a thrombotic event, family history of thrombosis, relative known to have the prothrombin (factor II) mutation, presence of another known genetic hypercoagulability in an individual with a history of thrombosis, and prior to major surgery, pregnancy, oral contraceptive use or estrogen therapy if there is a personal or family history of thrombosis.

     Testing for Factor II and Factor V-Leiden gene mutation is available at Ingalls Hospital Molecular Diagnostic Laboratory.  These mutations are detected by the Invader Assay (Third Wave Technologies) using Fluorescence Resonance Energy Transfer (FRET) Detection.

Mutations other than the Factor II or V Leiden  Gene Mutation that may cause elevated prothrombin and/or increased risk of venous thrombosis are not ruled out by this assay.

Due to the unique nature of genetic susceptibility testing patients should receive pre-test and post-test counseling.      

     These tests are reported as: negative, heterozygous, or homozygous.

     For any questions please call the Department of Pathology and Laboratory Services at Ingalls Hospital (708) 915-5763.



 Ancillary Testing in Urinary Cytopathology:  The UroVysion™ Test 

     Bladder neoplasms comprise 2 to 6 percent of all tumors. Men are affected more often than women (2.7 to 1) and Caucasians more often than people of other racial backgrounds. According to statistics from the Surveillance, Epidemiology, and End Results (SEER) databank, the incidence has been rising steadily over the last 3 decades and more than 70,000 new cases/year are expected. The estimated death rate has also been rising, currently estimated to reach >14,000/year. Urinary cytopathology is useful for the detection and monitoring of patients with urothelial carcinoma. This approach is best applied to high-grade neoplasms, where nearly all of the features usually ascribed to cancerous cellscan be appreciated in adequate samples.

     Urinary cytopathology is less useful for the detection and monitoring of very low-grade neoplasms, primarily because most of these tumors are composed of cells lacking features of malignancy but also because not all of the cells have all of the features usually ascribed to low grade neoplasms even when these cells are present in the sample. Using urinary cytopathology, nearly all aggressive urothelial neoplasms can be detected in adequately sampled bladders, whether these neoplasms occur as primary or recurrent tumors. The inability to detect low-grade neoplasms is not a major limitation to the use of urinary cytopathology, since low-grade lesions are rarely aggressive and can be readily detected cystoscopically. Considering the limitations of the methodology, urinary specimens are best classified in four basic categories: (1) negative, to include reactive cellular changes; (2) dysplastic cells, rule out low-grade neoplasm; (3) cells suspicious for a high grade neoplasm; (4) malignant tumor cells consistent with a high-grade neoplasm. Its limitations notwithstanding, urinary cytopathology is an important technique and should be integrated into every detection and monitoring program for neoplasms of the urinary bladder.

Ancillary testing:  Urothelial tissues and cells can be examined for their total DNA (ploidy), quantitative morphometric features, structural antigenic composition, genetic and chromosomal constitution, gene protein products, and presence and rate of DNA synthesis. Information is often obtained using immunohistochemistry and the light microscope. Other methods include enzyme-linked immunoabsorbent assay, fluorescence in situ hybridization and in situ hybridization, silver impregnation, instrumentation using computerized programs for capturing and reconstructing light scatter from dyes exposed to laser beams, laser capture microdissection, DNA (RNA) microarray analysis, and polymerase chain reactions.

Chromosomes and genes (Uro Vysion Testing). To date, no ancillary method of detection can distinguish between the low-grade, nonaggressive neoplasms that do not require early detection and treatment and the life-threatening high-grade aggressive urothelial neoplasms that do.  Most chromosomal and genetic aberrations are confined to high-grade carcinomas, raising the possibility of epiphenomena. Further, the ability to recognize a single genetically abnormal cell raises questions concerning the point at which early detection has meaningful implications for patient care. These caveats notwithstanding, a great deal of current interest has settled on the Vysis test (UroVysion) using FISH technology. This test is FDA approved. Vysis FISH is basically a cytogenetics test that searches for abnormalities in chromosomes 3,7,9,and 17. These particular chromosomes were chosen after screening with DNA array technology revealed high correlations with urothelial neoplasms, not because the chromosomes were necessarily suspected of being involved in the histogenesis of urothelial tumors.  The high rates of specificity and sensitivity documented in most publications are associated with rather low positive predictive values and may require the retesting of as many as 22% of specimens. In other words, a positive Vysis FISH result may NOT indicate the presence of a urothelial neoplasm in about 50% of patients being followed for this disease. Higher positive predictive values are achieved only by including specimens with cytologic abnormalities detected under the light microscope. When Vysis FISH is used to screen patients with hematuria, the positive predictive values are dismal (<10% to about 25%). Once usable preparations are obtained, the observer must carefully record at least 25 nuclei (under oil) to register a positive result and it is necessary to examine all urothelial nuclei in the specimen to assure a negative result. In most instances, Vysis FISH apparently does not detect cells that are invisible to cytopathologists but this method does accept a lower threshold for positive and simplifies the analysis. Nevertheless, Vysis FISH might well be beneficial to certain patients, for example those with suspicious or dysplastic cells in their voided urines and those at very high risk for recurrent high-grade urothelial carcinoma. The test should not be used as the only method of detection and a urinary cytopathology analysis should be performed on the same specimen if at all feasible.

 For any questions please call the Department of Pathology and Laboratory Services at Ingalls Hospital (708) 915-5763. 

* Taken and modified from the Narrative Syllabus “PRACTICAL APPROACHES TO BLADDER CANCER IN THE INFORMATION AGE”; by William M. Murphy, M. D.; Consultant, Urologic Pathology; Professor of Pathology, Emeritus; University of Florida, Gainesville. FL (Presented at the ASCP meeting, May 2010, Toronto).