A 54-year-old man presents to the emergency room with severe shortness of breath. Chest x-ray shows cardiomegaly with prominent thickening of the left ventricle wall. If a biopsy were taken of the myocardium which of the the following cellular responses would likely be seen microscopically?

• Atrophy

• Hypertrophy

• Hyperplasia

• Dysplasia

Answer explanation

Hypertrophy is the process where cells in an organ or tissue increase in size. Heart muscle becomes thickened (hypertrophied) when cardiac mass increases due to prolonged and increased stress on the heart. Hypertrophic myocardial cells show nuclear enlargement, bizarre nuclei and binucleation. Be able to recognize both the gross features of a hypertrophic heart (entire heart or cut sections) and microscopic/histologic features.

Cardiac atrophy would be characterized by ventricular wall thinning and decrease in myocyte cell size. Causes of cardiac atrophy include anorexia (e.g. cancer patient becoming cachectic) , prolonged bed rest or anything that chronically reduces the cardiac workload.

Cardiac myocytes are not able to regenerate and thus by definition are not able to undergo hyperplasia which is defined as an increase in the number of cells or reproduction rate of cells.

Dysplasia is defined as an increase in abnormal cell growth or development. In many organs it may indicate a precancerous state. However, not all dysplasias lead to cancer.

In the heart, arrhythmogenic right ventricular dysplasia refers to a disease in which fatty fibrous tissue replaces normal heart muscle. X-linked cardiac valvular dysplasia refers to the abnormal development of heart valves.

A 65-year-old woman with worsening chronic obstructive pulmonary disease has a lung biopsy performed due to a "change in the bronchial tissue" noted on X-ray (see H&E image from https://www.meddean.luc.edu/lumen/meded/MEDICINE/PULMONAR/images/path2/sld23.jpg). This change is best described as:

• Atrophy

• Dysplasia

• Hyperplasia

• Metaplasia

Answer explanation

COPD is caused by the noxious effects of tobacco smoke, which leads to airway epithelial injury and the induction of changes such as squamous metaplasia (SM), the reversible replacement of the normal columnar epithelium by squamous epithelium.

Atrophy is defined as a decrease in the size of a tissue or organ due to cellular shrinkage; the decrease in cell size is caused by the loss of organelles, cytoplasm and proteins.

Dysplasia is abnormal cells within a tissue or organ. It is not cancer, but it may develop into cancer and is sometimes referred to as precancer. 

Hyperplasia is an increase in the number of cells in a tissue or organ without tumor formation. It differs from HYPERTROPHY, which is an increase in bulk without an increase in the number of cells.

A 14-year-old boy comes to the physician because of inability to play soccer due to weakness in his legs which have become progressivelyworse over the past 6 months. Vital signs are within normal limits. Physical examination and electromyography shows markedly decreased muscle strength of the all extremities. A muscle biopsy is done, and shows a reduction in myofiber diameter with rounded to angular with hypereosinophilic sarcoplasm. These findings likely represent:

• Atrophy

• Hypertrophy

• Hyperplasia

• Metaplasia

Answer explanation

Atrophy is defined as a decrease in the size of a tissue or organ due to cellular shrinkage; the decrease in cell size is caused by the loss of organelles, cytoplasm and proteins.

Hyperplasia is an increase in the number of cells in a tissue or organ without tumor formation. It differs from HYPERTROPHY, which is an increase in bulk without an increase in the number of cells.

Metaplasia is the replacement of one differentiated somatic cell type with another differentiated somatic cell type in the same tissue. Typically, metaplasia is triggered by environmental stimuli, which may act in concert with the deleterious effects of microorganisms and inflammation.

A 74-year-old woman with lupus nephritis has worsening azotemia and requires dialysis. Unfortunately, she codes prior to the procedure. At autopsy, a wedge shaped infarct is present in both kidneys. Microscopically, these lesions will most likely show which of the following types of necrosis?

• Fat

• Caseation

• Coagulation

• Liquefactive

Answer explanation

Coagulative necrosis generally occurs due to an infarct (lack of blood flow from an obstruction causing ischemia) and can occur in all the cells of the body except the brain. The heart, kidney, adrenal glands or spleen are good examples of coagulative necrosis.

Gross appearance: a pale segment may be seen in contrast to surrounding healthy tissues.

Microscopic appearance: in an H&E staining tissue, eosinophilia like-cell (cells presenting pink on a histology slide) will be noticeable. Anucleated cells (cells without a nucleus) should be observable with preserved cell outlines which usually allows for the cell type and organ to be identified.

Fat necrosis does not denote a type of necrosis pattern. Instead, it is used to describe the destruction of fat, for example, due to pancreatic lipases that have been released into the surrounding tissues where the pancreas itself is at risk along with the peritoneal cavity. Once the enzymes come into contact with fat cells, their plasma membrane is liquefied, releasing the fats/triglycerides. The fatty acids combine with calcium through a process called saponification. An insoluble salt is created and gives the appearance of a chalky-white area. Breast tissues and other tissues with high fat content can also have fat necrosis triggered by trauma, for example.

Gross appearance: soft chalky-white area.

Microscopic appearance: basophilic (bluish) calcium deposits are present. Anucleated adipocytes with a cytoplasm that is more pink and contains amorphous mass of necrotic material. Inflammation may also be present.

Caseous necrosis occurs when the immune system and body cannot successfully remove the foreign noxious stimuli. Tuberculosis is the most common example where there is an aberrant immune response. The immune system seals off the foreign matter by using fibroblasts and white blood cells such as lymphocytes, NK cells, dendritic cells and macrophages. A granuloma may form (which creates an encasing layer) which includes lymphocytes and Langhans giant cells (fusion of epithelioid cells). The organism is not killed but rather contained.

Gross appearance: a yellow-white soft cheesy sphere that is enclosed by a distinct border.

Microscopic appearance: a granuloma composed of a core that is necrotic and uniformly eosinophilic, which is surrounded by a border of activated macrophages and lymphocytes. The core is structureless and should have debris and lysed cells. Langhans giant cells may be seen, and inflammation should also be noticed and present. There is a fibrous case surrounding and enclosing the core; hence fibroblasts should also be seen.

Liquefactive necrosis can be seen in brain tissue that has undergone infarction and is also associated with gangrenous digits/extremities that become superinfected with bacterial, viruses, parasites or fungal infections. Unlike coagulative necrosis, liquefactive necrosis forms a viscous liquid mass as the dead cells are being digested. Cellular dissolution and digestion of dying cells may also release further enzymes, which speeds up the liquefying process. The enzymes responsible for liquefaction are derived from either bacterial hydrolytic enzymes or lysosomal hydrolytic enzymes. These are proteases (collagenases, elastases), DNases and lysosomal enzymes.

It is not fully explained why the nervous system displays liquefactive necrosis without the cause of an infection, but it is suggested that the nervous system does hold a higher amount of lysosomal content, which leads to autolysis and an increased opportunity for these enzymes to digest the cells in the brain.

Gross appearance: liquid-like layer can be seen; pus may be present. Yellowing, softening or swelling of the tissue should be seen. Malacia (softening, or loss of consistency) should be present. A cystic space should be present for tissue resolution.

Microscopic appearance: macrophages and neutrophils, both dead and alive, should be present. Debris and lysed cells should be seen with inflammation. Partial space should be filled with lipids and debris. There is a loss of neurons and glial cells, with the formation of clear space.

Case presentation (https://jmedicalcasereports.biomedcentral.com/articles/10.1186/s13256-023-04295-0)

A 4-and-a-half-year-old Caucasian girl was referred to the clinic with a liver biopsy report indicating a diagnosis of glycogen storage disease. Prior to being referred to our clinic, the patient had been under the care of pediatric gastroenterologists. The patient’s initial symptoms included chronic abdominal pain, constipation, and elevated liver transaminase. With the help of the pediatric gastroenterologists, cholestasis, Wilson disease, and autoimmune hepatitis were ruled out. Given that glycogen storage diseases type I and type III are the most common, we initially managed the patient with frequent feedings and a diet that included complex carbohydrates such as a corn starch supplement and a lactose restriction. Following an unfavorable growth velocity and hepatomegaly during the follow-up period, genetic analysis was conducted, which revealed a novel mutation of the phosphorylase kinase regulatory subunit beta gene— a c.C412T (P.Q138x) mutation. As the diagnosis of glycogen storage disease type IX was confirmed, the treatment regimen was altered to a high protein diet (more than 2 g/kg/day) and a low fat diet.

Conclusion

Given the mild and varied clinical manifestations of glycogen storage disease type IX, it is possible for the diagnosis to be overlooked. It is important to consider glycogen storage disease type IX in children who present with unexplained hepatomegaly and elevated transaminase levels. Furthermore, due to the distinct management of glycogen storage disease type IX compared with glycogen storage disease type I and glycogen storage disease type III, genetic analysis is essential for an accurate diagnosis. What is the most likely mode of inheritance for the glycogen storage diseases?

• Autosomal dominant

• Autosomal recessive

• X-linked recessive

• Mitochondrial

Answer explanation

Glycogen storage diseases (GSDs) (glycogenoses) are inborn metabolic disorders characterized by defects in enzymes or transport proteins that affect glycogen metabolism. The glycogen found in these disorders is abnormal in quantity, quality, or both. The most likely mode of inheritance for these diseases is autosomal recessive. For example, if both parents are known to be heterozygous for a GSD I-causing pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Heterozygotes (carriers) are usually asymptomatic. Carrier testing for at-risk family members, prenatal testing for a pregnancy at increased risk, and preimplantation genetic testing are possible if both pathogenic variants have been identified in an affected family member. See table for partial list of Glygenoses and note Inheritance column.

A 10-year-old boy is brought to the ER because of severe right lower abdominal pain for 5 hours. His temperature is 102.8°F. Abdominal examination shows rebound tenderness of the right lower quadrant. An ultrasound confirms appendicitis. He is admitted and taken to the OR for an appendectomy. Which of the following best describes the inflammatory process involved in this condition?

• Acute inflammation

• Chronic inflammation

• Granulomatous inflammation

• Eosinophilic inflammation

Answer explanation

Acute inflammation consists of a vascular and cellular reaction that delivers leukocytes and plasma proteins into the tissues where these cells and proteins get rid of the noxious substances that elicited the response.

Chronic inflammation is the prolonged reaction to persistent stimuli in which inflammation, tissue injury and scarring usually coexist.

Granulomatous inflammation is a special type of chronic inflammation in which macrophages are strongly activated either by T cells or by recognition of persistent foreign bodies. Granulomas are more often seen in Crohn disease, tuberculosis and fungal infections.

Eosinophilic inflammation results from the dysregulation of biological mechanisms involved with eosinophil recruitment and activation and describes several biological mechanisms that enable eosinophils to infiltrate patients’ tissue to drive and worsen disease.

There is a broad range of diseases where eosinophils can play a central role e.g. Eosinophilic Asthma, Eosinophilic esophagitis, Nasal polyps, Eosinophilic granulomatosis with polyangiitis (EGPA), Hypereosinophilic syndrome, and some healthcare providers may not recognise this underlying connection.

This low awareness can negatively impact patients, who often spend too long in primary and secondary care before they get referred to the right specialist who can accurately diagnose and appropriately treat their illness.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4421734/

A 64-year-old man with end-stage kidney disease (ESRD) underwent deceased donor kidney transplantation 5 years after initiating hemodialysis. Serology testing immediately prior to transplant indicated presence of immunoglobulin G (IgG) antibodies to CMV, Epstein–Barr virus (EBV) and Varicella Zoster virus. The donor tested negative for CMV antibody. ∼3 weeks postoperatively, his SCr rose to 2.4 mg/dL. Prerenal azotemia was suspected in the setting of relatively poor fluid intake. A transplant kidney biopsy was performed and is shown in Figure 1 panels A and B. What is the most likely diagnosis?

• Herpes simplex virus

• Adenovirus

• Echovirus

• Cytomegalovirus

Answer explanation

Microscopically, CMV inclusions are quite distinctive from other viruses and are characterized by enlarged eosinophilic nuclei and granular cytoplasm (arrows). Cytomegalovirus (CMV) disease is a leading cause of infectious morbidity and mortality in patients with a kidney and other solid organ transplants as well as stem cell transplants. Before the advent of specific prophylaxis and therapy, more than half of the patients who had not been exposed to CMV prior to kidney transplantation developed primary disease and ∼20% of patients with prior evidence of exposure developed reactivation disease. Mortality estimates from CMV disease exceeded 30%. Although use of prophylaxis or preemptive treatment of detectable viral load has drastically reduced its burden, CMV remains a common clinical problem with a wide variety of presentations. Donors that are negative for CMV antibodies can transmit disease if they are unknowingly acutely infected.

A 1-year-old caucasian girl is brought to the emergency department by her parents due to bloody diarrhea.

Physical examination revealed an alert but irritable and ill-appearing child with a normal body temperature, heart rate of 130 beats/min, blood pressure of 90/60 mm Hg, and oxygen saturation by pulse oximetry of 95%.

Laboratory studies show:

 

Hemoglobin 8.0 g/dL (N=11.3–13.7) Hematocrit 24% (N=31–39) Leukocyte count 22,500/mm³ (N=6000–17,000) Platelet count 30,000/mm³ (N=150,000–400,000)Serum creatinine2.1 mg/dL (N=0.6–1.2)

A peripheral blood smear shows fragments/schistocytes, neutrophilia and thrombocytopenia. The red cell abnormality observed in this patient is most likely due to which of the following?

• Microangiopathic hemolytic anemia

• Sickle cell disease

• Hemoglobin C disease

• Essential Thrombocytosis

Answer explanation

Typical hemolytic uremic syndrome (HUS) is a leading cause of community acquired acute kidney injury in infants and young children. It is defined as a triad of microangiopathic hemolytic anemia (**fragments/schistocytes seen on peripheral blood smear**), thrombocytopenia and renal insufficiency associated with Shiga toxin-producing Escherichia coli.

Sickle cell RBCs appear abnormally sickle-shaped due to the precipitation of abnormal hemoglobin S. Other abnormalities seen in the peripheral blood smear of patients with SCD include Howell-Jolly bodies, nucleated red blood cells, and target cells.

In an oxygenized state, the hemoglobin C cell forms circulating intraerythrocytic crystals (tactoids) and has reduced solubility. In a deoxygenated state, virtually all hemoglobin C cells have crystalloid inclusions. Deoxygenation further reduces cell solubility and increases blood viscosity.

According to the World Health Organization, essential thrombocytosis is a disease that occurs when the platelet count is more than 450000 with the presence of Janus kinase 2 (JAK2), Calreticulin (CALR) or myeloproliferative leukemia virus oncogene (MPL) mutation, lacking clonal or reactive causes.

A 30-year-old Filipina woman complains of headache and dizziness for the past week. On presentation, her temperature is 38.8°C (101.8°F) and physical examination shows petechiae on the oral mucosa and multiple ecchymoses were present on the bilateral lower extremities. Pallor and pale conjunctivae were found. A systolic ejection murmur grade 3/6 at bilateral upper parasternal borders was heard. No hepatosplenomegaly was palpated. No malar rash or other type of rash was present on sun-exposed areas. No tenderness or deformities were present in the joints. Neurological examination was normal. There was no evidence of active oral, vaginal or rectal bleeding. Laboratory studies show:

Hemoglobin 7 g/dL Hematocrit 21% Mean corpuscular volume 85 μm³ Reticulocyte count 5% of red cells Leukocyte count 7000/mm³

Platelet count 15,000/mm³ Prothrombin time (INR) 12 sec (1.2) Partial thromboplastin time 31 sec

A peripheral blood smear showed fragments/schistocytes. Which of the following is the most likely cause of these findings?

• Immune thrombocytopenic purpura

• Thrombotic thrombocytopenic purpura

• Pernicious anemia

• Pancytopenia

Answer explanation

Case taken from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4336900/

Thrombotic thrombocytopenic purpura (TTP) is a thrombotic microangiopathy, which can be classified as idiopathic or in association with other disorders.^1–3 Acquired TTP is more common than the congenital type and is caused by autoantibodies targeting ADAMTS13. Antiplatelet drugs, immunosuppressive agents, HIV, estrogen-containing birth control, and pregnancy are the most commonly listed triggers for ADAMTS13 autoantibody formation causing acquired TTP. Deficiency of ADAMTS13, due to autoimmune inhibitors in patients with acquired TTP and mutations of the ADAMTS13 gene in hereditary cases, leads to VWF–platelet aggregation and microvascular thrombosis of TTP. Measuring ADAMTS13 activity level may aid in diagnosis. An accurate diagnosis of an underlying disease is essential to guide prompt intervention. Despite rare coincidence, connective tissue diseases, particularly systemic lupus erythematosus (SLE), have been associated with TTP. Distinguishing between SLE and TTP is challenging due to shared clinical features including haemolytic anaemia and thrombocytopenia. Without timely recognition and intervention, TTP poses high mortality. The mainstay of treatment in TTP is plasma exchange (Plasma provides the missing ADAMTS13 metalloproteinase which allows for the high molecular weight VWF multimers to be cleaved appropriately). Even with treatment, SLE-associated TTP was reported to have a higher mortality, 34–62.5%, compared to idiopathic TTP, which was about 20% mortality. Some small studies showed a benefit of adding other immunosuppressive agents in SLE-associated TTP. A diagnosis of SLE is important regarding overall care of the patient, maintenance therapy, surveillance of disease activity and fatal complications. More severe disease activity in SLE includes a higher incidence of TTP.

A 52-year-old man comes to the physician because of severe back pain, blurry vision, dizziness and headaches that have worsened over the past 6 weeks. Physical examination shows tenderness over the entire skull, lumbar spine and sacral spine . X-rays show osteolytic lesions involving the skull and spine. The total protein is markedly elevated. The CBC shows moderate pancytopenia and the peripheral blood smear shows marked rouleaux. Which of the following is the most likely diagnosis?

• Multiple myeloma

• Osteoarthritis

• Osteosarcoma

• Chondritis

Answer explanation

The clinical scenario is suggestive of multiple myeloma. Typical symptoms are bone pain, malaise, anemia, renal insufficiency, and hypercalcemia. Incidental discovery on comprehensive laboratory panels is common. The disease is diagnosed with serum or urine protein electrophoresis or immunofixation and bone marrow aspirate analysis. Skeletal radiographs are important in staging multiple myeloma and revealing lytic lesions, vertebral compression fractures, and osteoporosis. Magnetic resonance imaging and positron emission tomography or computed tomography are emerging as useful tools in the evaluation of patients with myeloma; magnetic resonance imaging is preferred for evaluating acute spinal compression.

Laboratory Findings

Anemia (mostly normocytic normochromic) is seen in 75% of patients. Peripheral blood examination shows increased background staining and rouleaux formation. Circulating plasma cells and a leuko-erythrobalstic picture are occasionally seen. Because of increased immunoglobulins, the ESR is high: >20 mm/hour in 85% and >100 in one third.Elevated creatinine is seen in 50% and hypercalcemia in 25%. Urinalysis is typically negative (Bence-Jones proteins are not detected by dipstick) unless there is amyloidosis or light chain deposition disease leading to albuminuria. Also, 24-hour urine is required for quantification of monoclonal proteins (M- proteins) or light chains.

An M-protein and/or light chain in the serum and/or urine is found in 97% of the patients. These usually present as a single peak in the gamma (or beta or alpha-2) region on densitometry or as a discrete band on agarose gel electrophoresis. Immunofixation (IF) is used to confirm their presence and determine their subtype. A serum free light chain (FLC) assay is useful in detecting patients with no monoclonal bands on electrophoresis and/or IF. Myeloma is classified into different types depending on their immunoglobulin heavy chain and light chain as follows: IgG (52%), IgA (21%), light chain (16%), Bi-clonal (2%), and IgM (0.5%), while IgD and IgE are rare.Patients with light chain myeloma are more prone to develop renal failure. About 3% of patients have non-secretory myeloma.

BM aspirate and biopsy show increased numbers of clonal plasma cells. Immunophenotyping using flow-cytometry and immunohistochemistry is important in proving clonality and can also provide some prognostic information.