Breast Cancer Pathology: Understanding the Histological Features

Breast cancer pathology involves examining the histological features of the cancer cells to determine the underlying diagnosis. The invasive component of breast cancer is typically made up of ductal cells, although invasive lobular cancer may also occur. In situ lesions, such as DCIS, may also be present.

When examining breast cancer pathology, several typical changes are seen in conjunction with invasive breast cancer. These include nuclear pleomorphism, coarse chromatin, angiogenesis, invasion of the basement membrane, dystrophic calcification (which may be seen on mammography), abnormal mitoses, vascular invasion, and lymph node metastasis.

To grade the primary tumor, a scale of 1-3 is used, with 1 being the most benign lesion and 3 being the most poorly differentiated. Immunohistochemistry for estrogen receptor and herceptin status is routinely performed to further understand the cancer’s characteristics.

The grade, lymph node stage, and size are combined to provide the Nottingham prognostic index, which helps predict the patient’s prognosis and guide treatment decisions. Understanding the histological features of breast cancer is crucial in determining the best course of treatment for patients.

Sickle cell disease can be definitively diagnosed through haemoglobin electrophoresis. In the case of a patient experiencing an acute haemolytic episode due to sickle cell disease, normocytic anaemia with a high reticulocyte count and the presence of Howell jolly bodies indicate hyposplenism. A peripheral smear showing sickle cells is also highly indicative of sickle cell disease, which is an autosomal recessive condition that may be present in other family members.

The osmotic fragility test is used to diagnose hereditary spherocytosis by exposing red blood cells to varying osmolarity and observing their fragility. Plasma folate deficiency can lead to macrocytic anaemia, but this is not the case in sickle cell disease. Flow cytometry is not useful in diagnosing sickle cell disease, but it can be used to classify leukemias and diagnose paroxysmal nocturnal haemoglobinuria.

If an autoimmune cause is suspected, a Coombs test can be performed to confirm the pathogenesis, as in the case of haemolytic disease of the newborn. Haemoglobin electrophoresis is one of the definitive tests for diagnosing sickle cell trait and disease, as it shows a decrease in normal haemoglobin A and the presence of haemoglobin S. Genetic analysis can also confirm the diagnosis.

Understanding Sickle-Cell Anaemia

Sickle-cell anaemia is a genetic disorder that occurs when an abnormal haemoglobin chain, known as HbS, is synthesized due to an autosomal recessive condition. This condition is more common in people of African descent, as the heterozygous condition offers some protection against malaria. In the UK, around 10% of Afro-Caribbean individuals are carriers of HbS. Symptoms in homozygotes typically do not develop until 4-6 months when the abnormal HbSS molecules take over from fetal haemoglobin.

The pathophysiology of sickle-cell anaemia involves the substitution of the polar amino acid glutamate with the non-polar valine in each of the two beta chains (codon 6) of haemoglobin. This substitution decreases the water solubility of deoxy-Hb, causing HbS molecules to polymerize and sickle in the deoxygenated state. HbAS patients sickle at p02 2.5 – 4 kPa, while HbSS patients sickle at p02 5 – 6 kPa. Sickle cells are fragile and can cause haemolysis, block small blood vessels, and lead to infarction.

To diagnose sickle-cell anaemia, haemoglobin electrophoresis is the definitive test. It is essential to understand the pathophysiology and symptoms of sickle-cell anaemia to provide appropriate care and management for affected individuals.

The correct answer is T lymphocytes, as the thymus plays a role in their maturation. DiGeorge syndrome is caused by a microdeletion on chromosome 22, resulting in the failure of development of the third and fourth pharyngeal arches. The syndrome is characterized by cardiac abnormalities, abnormal facies, thymus aplasia, cleft palate, and hypoparathyroidism, which can be remembered with the acronym CATCH.

The Thymus Gland: Development, Structure, and Function

The thymus gland is an encapsulated organ that develops from the third and fourth pharyngeal pouches. It descends to the anterior superior mediastinum and is subdivided into lobules, each consisting of a cortex and a medulla. The cortex is made up of tightly packed lymphocytes, while the medulla is mostly composed of epithelial cells. Hassall’s corpuscles, which are concentrically arranged medullary epithelial cells that may surround a keratinized center, are also present.

The inferior parathyroid glands, which also develop from the third pharyngeal pouch, may be located with the thymus gland. The thymus gland’s arterial supply comes from the internal mammary artery or pericardiophrenic arteries, while its venous drainage is to the left brachiocephalic vein. The thymus gland plays a crucial role in the development and maturation of T-cells, which are essential for the immune system’s proper functioning.

The cervix is drained by the internal iliac lymph nodes. These nodes are responsible for draining the pelvic structures, including the cervix and lower part of the uterus, making them the most likely location for lymphatic spread. They also drain the lower part of the rectum and the anal canal above the pectinate line. The deep inguinal nodes are not involved in this process as they receive drainage from the lower extremity and perineum. The inferior mesenteric nodes primarily drain the hindgut structures, while the para-aortic nodes drain the ovaries, which develop in the abdomen and move down the posterior abdominal wall during fetal development.

Lymphatic drainage is the process by which lymphatic vessels carry lymph, a clear fluid containing white blood cells, away from tissues and organs and towards lymph nodes. The lymphatic vessels that drain the skin and follow venous drainage are called superficial lymphatic vessels, while those that drain internal organs and structures follow the arteries and are called deep lymphatic vessels. These vessels eventually lead to lymph nodes, which filter and remove harmful substances from the lymph before it is returned to the bloodstream.

The lymphatic system is divided into two main ducts: the right lymphatic duct and the thoracic duct. The right lymphatic duct drains the right side of the head and right arm, while the thoracic duct drains everything else. Both ducts eventually drain into the venous system.

Different areas of the body have specific primary lymph node drainage sites. For example, the superficial inguinal lymph nodes drain the anal canal below the pectinate line, perineum, skin of the thigh, penis, scrotum, and vagina. The deep inguinal lymph nodes drain the glans penis, while the para-aortic lymph nodes drain the testes, ovaries, kidney, and adrenal gland. The axillary lymph nodes drain the lateral breast and upper limb, while the internal iliac lymph nodes drain the anal canal above the pectinate line, lower part of the rectum, and pelvic structures including the cervix and inferior part of the uterus. The superior mesenteric lymph nodes drain the duodenum and jejunum, while the inferior mesenteric lymph nodes drain the descending colon, sigmoid colon, and upper part of the rectum. Finally, the coeliac lymph nodes drain the stomach.

Understanding Burkitt’s Lymphoma

Burkitt’s lymphoma is a type of high-grade B-cell neoplasm that can occur in two major forms. The endemic or African form typically affects the maxilla or mandible, while the sporadic form is commonly found in the abdomen, particularly in patients with HIV. The development of Burkitt’s lymphoma is strongly associated with the c-myc gene translocation, usually t(8:14), and the Epstein-Barr virus (EBV) is also implicated in its development.

Microscopy findings of Burkitt’s lymphoma show a starry sky appearance, characterized by lymphocyte sheets interspersed with macrophages containing dead apoptotic tumor cells. Management of this condition involves chemotherapy, which can produce a rapid response but may also cause tumor lysis syndrome. To reduce the risk of this occurring, rasburicase, a recombinant version of urate oxidase, is often given before chemotherapy. Complications of tumor lysis syndrome include hyperkalemia, hyperphosphatemia, hypocalcemia, hyperuricemia, and acute renal failure.

In summary, Burkitt’s lymphoma is a serious condition that can occur in two major forms and is associated with c-myc gene translocation and the Epstein-Barr virus. Microscopy findings show a characteristic appearance, and management involves chemotherapy with the use of rasburicase to reduce the risk of complications.

Anaphylactic blood transfusion reactions are known to be associated with IgA deficiency, which increases the risk of such reactions. Classic symptoms include sudden onset shortness of breath, angioedema, and wheeze, and require immediate treatment with intramuscular adrenaline, followed by IV hydrocortisone and chlorphenamine to prevent a secondary reaction. Other conditions such as adult polycystic kidney disease, HIV infection, and liver cirrhosis are not known to be associated with anaphylactic blood transfusion reactions.

Blood product transfusion complications can be categorized into immunological, infective, and other complications. Immunological complications include acute haemolytic reactions, non-haemolytic febrile reactions, and allergic/anaphylaxis reactions. Infective complications may arise due to transmission of vCJD, although measures have been taken to minimize this risk. Other complications include transfusion-related acute lung injury (TRALI), transfusion-associated circulatory overload (TACO), hyperkalaemia, iron overload, and clotting.

Non-haemolytic febrile reactions are thought to be caused by antibodies reacting with white cell fragments in the blood product and cytokines that have leaked from the blood cell during storage. These reactions may occur in 1-2% of red cell transfusions and 10-30% of platelet transfusions. Minor allergic reactions may also occur due to foreign plasma proteins, while anaphylaxis may be caused by patients with IgA deficiency who have anti-IgA antibodies.

Acute haemolytic transfusion reaction is a serious complication that results from a mismatch of blood group (ABO) which causes massive intravascular haemolysis. Symptoms begin minutes after the transfusion is started and include a fever, abdominal and chest pain, agitation, and hypotension. Treatment should include immediate transfusion termination, generous fluid resuscitation with saline solution, and informing the lab. Complications include disseminated intravascular coagulation and renal failure.

TRALI is a rare but potentially fatal complication of blood transfusion that is characterized by the development of hypoxaemia/acute respiratory distress syndrome within 6 hours of transfusion. On the other hand, TACO is a relatively common reaction due to fluid overload resulting in pulmonary oedema. As well as features of pulmonary oedema, the patient may also be hypertensive, a key difference from patients with TRALI.

The clotting cascade is an example of a positive feedback mechanism, where the presence of clotting factors attracts further clotting factors until a functioning clot is formed. On the other hand, blood sugar, blood pressure, and cortisol are controlled via negative feedback mechanisms. When blood sugar rises, insulin is released to transport glucose into cells, lowering blood sugar. When BP is low, the RAAS is activated to increase BP through vasoconstriction and retention of salt and water. Cortisol is released in response to ACTH, which is inhibited by high levels of cortisol through negative feedback on the hypothalamus and anterior pituitary.

The Coagulation Cascade: Two Pathways to Fibrin Formation

The coagulation cascade is a complex process that leads to the formation of a blood clot. There are two pathways that can lead to fibrin formation: the intrinsic pathway and the extrinsic pathway. The intrinsic pathway involves components that are already present in the blood and has a minor role in clotting. It is initiated by subendothelial damage, such as collagen, which leads to the formation of the primary complex on collagen by high-molecular-weight kininogen (HMWK), prekallikrein, and Factor 12. This complex activates Factor 11, which in turn activates Factor 9. Factor 9, along with its co-factor Factor 8a, forms the tenase complex, which activates Factor 10.

The extrinsic pathway, on the other hand, requires tissue factor released by damaged tissue. This pathway is initiated by tissue damage, which leads to the binding of Factor 7 to tissue factor. This complex activates Factor 9, which works with Factor 8 to activate Factor 10. Both pathways converge at the common pathway, where activated Factor 10 causes the conversion of prothrombin to thrombin. Thrombin hydrolyses fibrinogen peptide bonds to form fibrin and also activates factor 8 to form links between fibrin molecules.

Finally, fibrinolysis occurs, which is the process of clot resorption. Plasminogen is converted to plasmin to facilitate this process. It is important to note that certain factors are involved in both pathways, such as Factor 10, and that some factors are vitamin K dependent, such as Factors 2, 7, 9, and 10. The intrinsic pathway can be assessed by measuring the activated partial thromboplastin time (APTT), while the extrinsic pathway can be assessed by measuring the prothrombin time (PT).

Methotrexate treatment can lead to megaloblastic macrocytic anemia due to a deficiency of folate.

The patient’s low hemoglobin and high MCV indicate macrocytic anemia, which can be caused by various factors such as alcohol abuse, hypothyroidism, aplastic anemia, and megaloblastic anemia due to a deficiency of vitamin B12 and/or folate. In this case, the patient has a history of rheumatoid arthritis and takes methotrexate weekly, which inhibits dihydrofolate reductase and causes a deficiency of folate. Therefore, folate deficiency is the most probable cause of the patient’s anemia.

Alcohol excess is an incorrect option as it usually requires larger quantities of alcohol to cause macrocytic anemia.

Anaemia of chronic disease is an incorrect option as it typically results in normocytic or microcytic anemia, not macrocytic anemia.

Iron deficiency anemia is an incorrect option as it causes microcytic anemia, and the MCV value would be lower than expected.

Understanding Macrocytic Anaemia

Macrocytic anaemia is a type of anaemia that can be classified into two categories: megaloblastic and normoblastic. Megaloblastic anaemia is caused by a deficiency in vitamin B12 or folate, which leads to the production of abnormally large red blood cells in the bone marrow. This type of anaemia can also be caused by certain medications, alcohol, liver disease, hypothyroidism, pregnancy, and myelodysplasia.

On the other hand, normoblastic anaemia is caused by an increase in the number of immature red blood cells, known as reticulocytes, in the bone marrow. This can occur as a result of certain medications, such as methotrexate, or in response to other underlying medical conditions.

It is important to identify the underlying cause of macrocytic anaemia in order to provide appropriate treatment. This may involve addressing any nutritional deficiencies, managing underlying medical conditions, or adjusting medications. With proper management, most cases of macrocytic anaemia can be successfully treated.

The bone marrow in large bones is responsible for the production of human red blood cells through erythropoiesis. Stem cells undergo a 7-day development process to become red blood cells, which then circulate for around 120 days before being eliminated by the spleen. Eryptosis, or programmed red cell death, occurs at the same rate as production.

However, certain diseases can increase the rate of eryptosis, resulting in a shorter lifespan for red blood cells. These diseases include haemolytic uraemic syndrome, sepsis, malaria, sickle cell disease, thalassaemia, iron deficiency, and Wilson’s disease.

Iron deficiency anaemia is a prevalent condition worldwide, with preschool-age children being the most affected. The lack of iron in the body leads to a decrease in red blood cells and haemoglobin, resulting in anaemia. The primary causes of iron deficiency anaemia are excessive blood loss, inadequate dietary intake, poor intestinal absorption, and increased iron requirements. Menorrhagia is the most common cause of blood loss in pre-menopausal women, while gastrointestinal bleeding is the most common cause in men and postmenopausal women. Vegans and vegetarians are more likely to develop iron deficiency anaemia due to the lack of meat in their diet. Coeliac disease and other conditions affecting the small intestine can prevent sufficient iron absorption. Children and pregnant women have increased iron demands, and the latter may experience dilution due to an increase in plasma volume.

The symptoms of iron deficiency anaemia include fatigue, shortness of breath on exertion, palpitations, pallor, nail changes, hair loss, atrophic glossitis, post-cricoid webs, and angular stomatitis. To diagnose iron deficiency anaemia, a full blood count, serum ferritin, total iron-binding capacity, transferrin, and blood film tests are performed. Endoscopy may be necessary to rule out malignancy, especially in males and postmenopausal females with unexplained iron-deficiency anaemia.

The management of iron deficiency anaemia involves identifying and treating the underlying cause. Oral ferrous sulfate is commonly prescribed, and patients should continue taking iron supplements for three months after the iron deficiency has been corrected to replenish iron stores. Iron-rich foods such as dark-green leafy vegetables, meat, and iron-fortified bread can also help. It is crucial to exclude malignancy by taking an adequate history and appropriate investigations if warranted.

Dilutional anemia can occur as a result of saline administration, which does not improve oxygen transport or coagulopathy.

When the blood group of a patient is unknown, O rhesus negative blood may be administered as it is considered the universal donor. However, to conserve O negative blood stocks, transfusion guidelines now recommend giving male patients O positive blood in such situations, as Rhesus status is only relevant in pregnancy.

It is crucial to ensure that the correct blood product is prescribed and administered to the right patient, as transfusion reactions can be severe and fatal.

Blood Products and Cell Saver Devices

Blood products are essential in various medical procedures, especially in cases where patients require transfusions due to anaemia or bleeding. Packed red cells, platelet-rich plasma, platelet concentrate, fresh frozen plasma, and cryoprecipitate are some of the commonly used whole blood fractions. Fresh frozen plasma is usually administered to patients with clotting deficiencies, while cryoprecipitate is a rich source of Factor VIII and fibrinogen. Cross-matching is necessary for all blood products, and cell saver devices are used to collect and re-infuse a patient’s own blood lost during surgery.

Cell saver devices come in two types, those that wash the blood cells before re-infusion and those that do not. The former is more expensive and complicated to operate but reduces the risk of re-infusing contaminated blood. The latter avoids the use of donor blood and may be acceptable to Jehovah’s witnesses. However, it is contraindicated in malignant diseases due to the risk of facilitating disease dissemination.

In some surgical patients, the use of warfarin can pose specific problems and may require the use of specialised blood products. Warfarin reversal can be achieved through the administration of vitamin K, fresh frozen plasma, or human prothrombin complex. Fresh frozen plasma is used less commonly now as a first-line warfarin reversal, and human prothrombin complex is preferred due to its rapid action. However, it should be given with vitamin K as factor 6 has a short half-life.