How Do Pathologists Drive Accurate
Diagnoses & Personalized Treatment?
About the Doctor
Molecular Pathology & Hematopathology
Dr. Sameer Talwarkar is an American Board-Certified Pathologist with almost 20 years of experience practicing in the United States. He completed his pathology training in the U.S. with subspecialty training in Molecular Pathology & Hematopathology. He has worked at several renowned institutions, including the MD Anderson Cancer Center and the University of Pittsburgh. Currently, he serves as the Medical Director at a large reference laboratory in the Midwest, overseeing Molecular Pathology testing & Hematopathology services.
Role of a pathologist in modern medicine
A pathologist is referred to as a doctor’s doctor. The expertise of a pathologist plays a crucial role in the final diagnosis of a disease. The clinician primarily relies on a pathologist to confirm a diagnosis in serious conditions like cancer. Pathologists play an important role in guiding the patient through an accurate diagnosis. General anatomic pathologists (surgical pathologists) analyse the tissues removed during surgery. Clinical pathologists focus on testing the blood and other bodily fluids. Forensic pathologists perform autopsies in collaboration with the law to determine the cause of death. Thus, pathologists play a crucial role in modern medicine.
Atypical cells in a breast biopsy – Is it cancer?
A qualified pathologist must review the slides if the biopsy report mentions “atypical cells”. Breast lumps can be caused by several factors. Sometimes, cancer can be hidden within the lumps. Atypical cells indicate the need for further assessment. Additional testing like immunohistochemistry is often required to distinguish between benign and malignant cells.
Fluorescence in situ hybridization (FISH) can help to assess the grade of the tumor (whether high-grade or low-grade). These innovative techniques are available at specialized institutions, especially in the U.S. Atypical cells can be considered as a sign that necessitates further testing to make an accurate diagnosis.
Personalized medicine
A sample undergoes a set of diagnostic tests when received. Additional testing is conducted to analyze specific biomarkers if the results confirm cancer. The two main types of biomarkers include predictive and prognostic markers. Predictive markers determine how a patient responds to certain treatments. Prognostic markers provide insights related to outcomes of the disease, such as progression/risk of recurrence.
Immunohistochemistry, fluorescence in situ hybridization (FISH), and next-generation sequencing (NGS) are the techniques used by pathologists to identify these markers.
Tumor genotyping
In tumor genotyping, a tissue sample from a patient undergoes detailed genetic analysis. This process involves sequencing the genes within the tumor to detect specific genetic alterations. The driver genes play a role in enhancing the growth of cancer cells. The regulator genes influence how the tumor responds to treatment.
Through genotyping, pathologists can analyse whether the tumour harbours a genetic link to better or worse outcomes. The results that identify the predictive markers, such as HER2 (breast cancer) or KRAS mutations (colon cancer) are shared with the oncologists. These results guide personalized treatment decisions. For example, targeted therapies can be used to treat HER2-positive breast cancers. Certain targeted treatments are limited in KRAS mutations in colon cancer due to poor prognosis.
Gene therapy
Gene therapy has shown progress in conditions such as Duchenne muscular dystrophy and sickle cell disease. FDA-approved gene therapies are available for Duchenne muscular dystrophy that offer hope. Gene therapy is also indicated in sickle cell disease, which marks a major breakthrough in managing inherited genetic disorders.
Treatment for muscular dystrophy
Rare genetic disorders, known as germline mutations in genes responsible for muscle function, cause the most common forms of muscular dystrophy. There are no available curative treatments for most forms of muscular dystrophy.
Gene therapy is the only treatment option for Duchenne muscular dystrophy (DMD). The severity and progression can differ from one individual to another. Treatment options are based on symptoms, anchored to the specificity of each patient’s condition.
Specialised tests for tumor samples
Specialized tests are available in the U.S. that help predict a patient’s response to treatment. For example, genomic testing following a mammogram is used in breast cancer patients where the tumor is sequenced to identify the specific genes that are either upregulated or downregulated. Another test is PD-L1 immunohistochemistry, which helps determine the criteria for immunotherapy. Patients whose tumors test positive for PD-L1 respond better to immunotherapy drugs. Circulating tumor DNA (ctDNA) testing helps to analyse the fragments of tumor DNA found in the bloodstream.
What is immunotherapy
Immunotherapy targets the specific markers that are expressed on the tumor cells. Anti-PD-L1 therapies can be used to treat a tumor that expresses PD-L1. A common example is lung cancer, where PD-L1 testing has become necessary. Patients diagnosed with lung cancer should undergo PD-L1 testing to evaluate eligibility for immunotherapy that can include neoadjuvant treatment options.
FDA-approved immunotherapy can be used in breast cancer and melanoma, which are effective. Immunotherapy offers several benefits and is regarded as a cornerstone of cancer treatment. For instance, former U.S. President Jimmy Carter, who was treated with immunotherapy for melanoma, responded remarkably well, living nearly to the age of 100.
Immunohistochemistry testing
Immunohistochemistry (IHC) uses targeted antibodies to detect the specific antigens that are present in tumor cells. The antibodies bind to the antigens, which allows pathologists to detect the presence of certain markers. For instance, if a tumor expresses HER2 protein, a monoclonal antibody specific to HER2 is applied to the tissue sample. The tumor cells show a visible stain under the microscope if they are HER2 positive. This confirmation is important as HER2-positive patients are eligible for targeted treatments. Immunohistochemistry modifies the treatment plan that provides relevant information about the tumor.
Germline testing
Germline testing serves as a recent advancement in clinical pathology. It has been used in managing certain cancers, especially in patients with a family history of cancer. Typically, pathologists collect normal cells from peripheral blood or a buccal swab for germline testing. This helps in identifying the genetic variants that indicate a predisposition to certain cancers and guides treatment decisions. Germline testing uses normal or circulatory cells, while tumour genotyping focuses on cancer cells
Flow cytometry
Flow cytometry is a diagnostic tool used for detecting blood cancers. In this method, cells go through a thin tube in a flow cytometer, where each cell is examined based on its physical features and then stained with fluorescent antibodies. These antibodies target specific markers on the surface of the cells. Flow cytometry helps to detect and categorize the abnormal cells that allow for accurate subtyping of blood cancer.
Role of complete blood count (CBC)
A complete blood count (CBC) helps assess the patient’s overall health, particularly when analysed with red cell indices and differential count. Mean corpuscular volume (MCV) is a key parameter that helps in assessing the size of red blood cells. A low MCV can indicate iron deficiency anaemia. Haemoglobinopathies, like thalassaemia, serve as an important consideration. Patients with chronic anaemia should undergo haemoglobin electrophoresis to screen for disorders even if CBC is normal. Evaluation of white blood cells (WBC) is also necessary in addition to red blood cells (RBC). An increase in lymphocyte count can indicate both benign and malignant conditions. Hence, analysis of the complete blood profile is essential for accurate diagnosis and treatment.
Reduced platelet count and bruising
The first step is to rule out pseudothrombocytopenia when a CBC shows reduced platelet count. This condition occurs due to clumping of platelets that can result from inadequate anticoagulation or inaccurate collection of samples. Clumping can also result from poorly prepared smears. If the patient also has bruising, it raises the concern that the reduced platelet count is genuine. In this situation, it is better to refer the patient to a hematologist for further evaluation. Other tests, such as platelet function assays, anti-platelet antibody testing, etc., can determine whether the cause is an autoimmune condition like immune thrombocytopenia or another hematologic disorder.
Role of blood tests in detecting early cancer
In chronic conditions like chronic lymphocytic leukemia, blood tests that indicate reduced platelet count and abnormal blood smear findings can indicate a chronic hematologic condition. The presence of atypical lymphocytes necessitates additional testing like flow cytometry. This test can help in detecting a small clonal populations of abnormal lymphocytes. Early diagnosis can initiate appropriate treatment plans.
Erythrocyte sedimentation rate & C-reactive protein
ESR and C-reactive protein are commonly used inflammatory markers. Elevation of these markers indicates the presence of an underlying inflammation that could be due to autoimmune diseases, chronic inflammatory conditions, or cancers.
Testing for rheumatoid arthritis
Lab tests and clinical examinations play an important role in diagnosing autoimmune conditions. The most common test is the ANA (antinuclear antibody) profile, which helps detect autoimmune diseases. A biopsy can be considered in cases of arthritis or rheumatoid nodules, particularly when symptoms are localised. Most of the autoimmune diseases can be diagnosed through blood tests, and a biopsy is not routinely required.
High levels of ALT and AST in a non-drinker
There is a misconception that increased liver function tests, such as ALT and AST levels are associated with alcohol use, which is not true. Non-alcoholic fatty liver disease (NAFLD) is the most common cause of elevated liver enzymes, particularly in the Indian subcontinent. Other causes include autoimmune hepatitis, hepatitis B, hepatitis C, and drug-induced liver injury. Hence, it is essential to conduct additional testing to rule out these conditions.
Tests for non-alcoholic fatty liver disease and hepatitis B & C
Antibody and antigen tests are available for hepatitis B & C. Vaccinated individuals against hepatitis B will have positive antibodies, indicating immunity. When there is doubt, antigen testing for hepatitis B & C is more crucial. Hepatitis A can occur due to food contamination and is less severe. Additional tests include an ANA profile to analyse autoimmune hepatitis, which can involve markers like anti-mitochondrial and anti-smooth muscle antibodies. Autoimmune hepatitis increases these markers, which can aid in diagnosis. For patients with non-alcoholic fatty liver disease (NAFLD), imaging studies like ultrasound aid in correlating with lab abnormalities.
Sudden rise in blood sugar and HbA1c
Diagnostic tests for diabetes include fasting glucose and HbA1c levels. HbA1c gives an average value of the blood sugar level over the past three months, and it also gives an idea regarding the person’s glycaemic control. In prediabetes or diabetes, both fasting glucose and HbA1c are increased. The results should be confirmed after repeated testing.
The chance of having diabetes is comparatively low if blood glucose levels are within the normal range. Consistent monitoring of blood glucose levels is essential in determining the diagnosis.
Hyperlipidaemia
Cholesterol is considered the body’s” burning fuel” due to its role in various physiological functions. High levels of cholesterol can lead to atherosclerosis, which enhances the risk of cardiovascular diseases. The lipid profile includes triglycerides, HDL, LDL, and total cholesterol. Triglycerides are the dietary fats we take, while HDL (high-density lipoprotein) is considered good cholesterol that has beneficial effects.
Low-density lipoprotein (LDL) can contribute to plaque build-up in the arteries. Very low-density lipoprotein (VLDL) also plays a role in the transportation of lipids. Assessing a full lipid profile helps to analyse an individual’s risk of heart disease and guides medical interventions.
Can T3 and T4 levels with abnormal TSH indicate hypothyroidism?
TSH is useful for evaluating thyroid disease. High TSH levels with normal T3 and T4 levels do not indicate hypothyroidism. It is essential to measure free T4, which is a sensitive indicator of thyroid function. T4 levels usually rise in hyperthyroidism. Elevated TSH with normal T3 & T4 can be seen in pituitary adenoma. The best way to confirm the abnormality is to repeat the TSH test. Testing of T3 and T4 must be done if it remains elevated for accurate diagnosis of hypothyroidism.
Tests for autoimmune thyroid diseases
Serum assays that analyse thyroid function, including TSH, T3, and free T4 levels, are used to diagnose Hashimoto’s and Graves’ diseases. Specific autoantibodies play a crucial role in the diagnosis of autoimmune thyroiditis. These antibodies include anti-thyroglobulin antibodies and anti-thyroid peroxidase (anti-TPO) antibodies that target the thyroid gland.
It is important to check the T3 and T4 levels in women at least once a year, as they are more prone to thyroid diseases.
Conclusion
Pathologists play an essential role in providing accurate diagnoses, individualised treatment programs, and innovative therapeutic approaches. From finding cancer biomarkers to recognizing autoimmune and genetic illnesses, they help physicians and oncologists make well-informed decisions.
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