Clinical History: A 57-year-old man presented to his primary care physician with a 3-month history of back pain and 2-week history of fatigue and weakness. Plain radiograph showed lytic lesions in multiple bones and urinalysis revealed Bence Jones protein. Laboratory analysis showed anemia. A bone marrow biopsy was performed and, based on the diagnosis, chemotherapy and radiation were initiated; however, the patient developed sepsis and died. Radiography, gross and microscopic images are provided.
Many of the bones contained poorly delineated, soft gelatinous red tumor masses of various dimensions. Plain film of the skull shows sharply punched out bone lesions.
The marrow is heavily infiltrated with plasma cells which vary in degree of maturation. Islets of normoblasts are present, but granulocytes and megakaryocytes are markedly decreased. There is considerable loss of trabecular and cortical bone.
A thin layer of compact/dense bone borders this section, with internal cancellous/spongy bone. The spaces between bony spicules are filled with hematopoietic cells. Not the large numbers of (round, empty) fat cells present within the marrow space. The fat is lost during processing into paraffin sections. Megakaryocytes can be readily identified, since they are approximately 5-fold larger than most bone marrow cells and contain strongly eosinophilic cytoplasm and multiple nuclei.
(slide and description courtesy of Dr. Laura Hale, Duke PATHOL725 course director)
Gross image questions:
Take a screenshot and annotate the lesions. Describe their appearance.
Radiology image questions:
Describe the number and quality of the lesions.
VM image questions:
Take a screenshot and annotate the periosteum, cortical bone, and bony trabeculae.
Describe the bone marrow and the predominant blood cell type seen.
What are the histologic features that help you identify the neoplastic cell type?
413-2. Which of the following additional findings is most likely in this patient?
CASE NUMBER 295, UMich slide 35996nl [DigitalScope] - courtesy of UMich
Clinical History: A 16-year-old boy presented to his pediatrician with a 3 cm mass on right side of his neck. This mass was biopsied. Following diagnosis, a screening CT was performed and revealed a mediastinal mass. Immunophenotyping gave the following results for the neoplastic cells: CD30+/CD15+/CD20-/CD45-. Gross and microscopic images of the neck mass biopsy are provided.
The normal lymph node architecture is completely destroyed. In its place are thick bands of collagen, separating islands of lymphoid tissue. In some of these nodules, there is a mixed infiltrate consisting of lymphocytes, eosinophils, some neutrophils and plasma cells, and numerous large cells with highly pleomorphic nuclei. Nuclei are frequently multi lobulated but classic binucleate Reed-Stemberg cells are uncommon. Many cells are so-called "lacunar variants", with nuclei which have artifactually shrunken away from their cytoplasmic borders, leaving a clear space than can often easily be appreciated at low power.
The lymph node contains a cortex which includes the lymphoid follicles and a medulla which is looser tissue containing the lymphatic channels and blood vessels.
Gross image questions:
Describe the pathologic changes and compare to what would be expected in a healthy lymph node.
VM image questions:
How does the patient’s lymph node differ from normal lymph node architecture (e.g., capsule, germinal centers, mantle zones, paracortex)? (You may find it helpful to review the normal lymph node VM)
Take a screenshot and annotate an example of a neoplastic cell. What are they called?
295-2. Which of the following is the proposed line of differentiation of the neoplastic cells?
Clinical History: A 65-year-old man presented to his primary care physician with a 6-month history of fatigue and weakness and a 2-month history of a burning/tingling sensation in both feet. Physical exam revealed pale mucous membranes and a reddened, smooth tongue. Laboratory analysis showed an increased MCV, a decreased hematocrit and serum antibodies to intrinsic factor. A peripheral smear and a subsequent gastric biopsy are provided for evaluation.
The prominent microscopic finding in this peripheral blood smear is the presence of a neutrophil with a nucleus showing at least seven segments. This is called hypersegmentation. The cytoplasm contains appropriate granules. The red blood cells show mild variation in size (anisocytosis). Some large, oval red blood cells are present, and these oval macrocytes show reduced central pallor. Central pallor is not increased in red cells overall. Platelets appear to have normal morphology.
The gastric biopsy shows loss of parietal cells and intestinal metaplasia. There is a deeply seated mixed inflammatory infiltrate consisting of lymphocytes, macrophages and plasma cells.
Scan around the 63x and 86x slides at high magnification to see the various kinds of blood cells that were discussed in the lecture. Most abundant, of course, are the red blood cells (RBCs) or erythrocytes, which are seen in large numbers everywhere you look. In between the RBCs you should look for small, basophilic fragments which are platelets or thrombocytes [example] that are important in blood clotting. As you continue viewing, you will see occasional white blood cells (leukocytes). Some of the white blood cells may defy identification, often because the cells were damaged during slide preparation, so look for characteristic examples, and ignore the equivocal cells. Refer to the images in your texts and from the lecture and try to find an example of each leukocyte type using the 63x and 86x slides (there's less area to cover in these high-mag slides and the cells present are excellent, although the 63x slide does NOT contain any basophils).
The most common white blood cell is the neutrophil, which has a distinct multi-lobed nucleus (often 3-5 lobes). Also frequently seen are lymphocytes, which are small cells (often as small as RBCs) with a dark nucleus and very little cytoplasm. Another cell type is the monocyte, the largest of the blood cells. It has a large, relatively pale nucleus, and rather clear cytoplasm (granules are usually less apparent than those in the illustration in W). You will also see an occasional eosinophil, with prominent reddish granules filling the cytoplasm, and a nucleus with 2 (or sometimes 3) lobes. The exact color of the granules may vary from slide to slide, depending on how well the slide was prepared. In your particular slides they may be anywhere from bright red to dull brown. The remaining cell type you may see on your slides is the basophil, which is hard to find, since it constitutes less than 1% of the leukocytes (the 86x slide actually has THREE excellent examples). The cytoplasm contains large, irregular granules in a "grape-cluster" appearance that usually stain dark blue or almost black. Basophil nuclei may often appear somewhat oval-shaped, so, at first glance, they may be confused with lymphocytes. However, the presence of the large, dark-staining granules should help you distinguish them; also, remember that basophils are rare.
After you've done some looking on your own, here some quick links showing examples of each type of leukocyte (in order of their normal frequency in a blood smear):
The normal gastric mucosa of the fundus contains superficial fovea arranged in leaf like fronds and deeper gastric glands. The foveolar cells secrete mucin. The gastric glands include mucous cells, parietal cells, chief cells and enteroendocrine cells.
VM questions:
Describe the peripheral blood smear.
Identify on an annotated screen shot and describe one of the neutrophils.
Do the red cells show anisocytosis or are they a homogeneous population?
Gastric biopsy still image questions:
On an annotated screenshot of the medium or high power gastric biopsy still image, identify pathologic changes shown in the gastric biopsy.
508-2. Which of the following is the most appropriate treatment?
CASE NUMBER 605, UMich slide 42610nl [DigitalScope] - courtesy of UMich
Clinical History: A 45-year old woman presents with marked splenomegaly. Her leukocyte count is increased to 300,000/uL. The differential count reveals the presence of small numbers of myeloblasts and promyelocytes, with a predominance of myelocytes, metamyelocytes, bands, and segmented neutrophils. Basophils are also increased in number, as are platelets. The patient is not anemic. Leukocyte alkaline phosphatase is decreased. A bone marrow biopsy is performed and a specimen is prepared for histopathology. A photomicrograph of the peripheral blood film is also provided.
The red cells show two populations – some are hypochromic while others are microspherocytic (small and without central pallor). The latter are likely transfused red cells. The white cells are almost all blasts. They vary from 1.5x to 3x the diameter of red cells, have large round to slightly indented nuclei which occupy almost the entire cell (very high nuclear to cytoplasmic ratio). They have fine or reticular nuclear chromatin, 1-3 nucleoli, and a small amount of cytoplasm, which is without granules in most blasts. Platelets are not seen.
Scan around the 63x and 86x slides at high magnification to see the various kinds of blood cells that were discussed in the lecture. Most abundant, of course, are the red blood cells (RBCs) or erythrocytes, which are seen in large numbers everywhere you look. In between the RBCs you should look for small, basophilic fragments which are platelets or thrombocytes [example] that are important in blood clotting. As you continue viewing, you will see occasional white blood cells (leukocytes). Some of the white blood cells may defy identification, often because the cells were damaged during slide preparation, so look for characteristic examples, and ignore the equivocal cells. Refer to the images in your texts and from the lecture and try to find an example of each leukocyte type using the 63x and 86x slides (there's less area to cover in these high-mag slides and the cells present are excellent, although the 63x slide does NOT contain any basophils).
The most common white blood cell is the neutrophil, which has a distinct multi-lobed nucleus (often 3-5 lobes). Also frequently seen are lymphocytes, which are small cells (often as small as RBCs) with a dark nucleus and very little cytoplasm. Another cell type is the monocyte, the largest of the blood cells. It has a large, relatively pale nucleus, and rather clear cytoplasm (granules are usually less apparent than those in the illustration in W). You will also see an occasional eosinophil, with prominent reddish granules filling the cytoplasm, and a nucleus with 2 (or sometimes 3) lobes. The exact color of the granules may vary from slide to slide, depending on how well the slide was prepared. In your particular slides they may be anywhere from bright red to dull brown. The remaining cell type you may see on your slides is the basophil, which is hard to find, since it constitutes less than 1% of the leukocytes (the 86x slide actually has THREE excellent examples). The cytoplasm contains large, irregular granules in a "grape-cluster" appearance that usually stain dark blue or almost black. Basophil nuclei may often appear somewhat oval-shaped, so, at first glance, they may be confused with lymphocytes. However, the presence of the large, dark-staining granules should help you distinguish them; also, remember that basophils are rare.
After you've done some looking on your own, here some quick links showing examples of each type of leukocyte (in order of their normal frequency in a blood smear):
Part 2, UMich slide 55182nl [DigitalScope] - courtesy of UMich
Clinical History (continued): She undergoes therapy with imatinib mesylate (tyrosine kinase inhibitor), which reduces the spleen size and brings the total leukocyte count within normal range. She remains in remission for 3 years and then begins to experience fatigue and a 10-kg weight loss. Physical examination now shows petechial hemorrhages. CBC shows hemoglobin of 10.5 g/dL, hematocrit 30%, platelet count 60,000 µL, and WBC count 40,000/µL. A peripheral blood film is shown in the virtual slide (UMich_55182nl) and illustrated in the image below. Karyotypic analysis shows two Ph chromosomes and aneuploidy. Flow cytometric analysis of the peripheral blood shows CD19+, CD10+, sIg-, CD3- cells.
The red cells show two populations – some are hypochromic while others are microspherocytic (small and without central pallor). The latter are likely transfused red cells. The white cells are almost all blasts. They vary from 1.5x to 3x the diameter of red cells, have large round to slightly indented nuclei which occupy almost the entire cell (very high nuclear to cytoplasmic ratio). They have fine or reticular nuclear chromatin, 1-3 nucleoli, and a small amount of cytoplasm, which is without granules in most blasts. Platelets are not seen.
Scan around the 63x and 86x slides at high magnification to see the various kinds of blood cells that were discussed in the lecture. Most abundant, of course, are the red blood cells (RBCs) or erythrocytes, which are seen in large numbers everywhere you look. In between the RBCs you should look for small, basophilic fragments which are platelets or thrombocytes [example] that are important in blood clotting. As you continue viewing, you will see occasional white blood cells (leukocytes). Some of the white blood cells may defy identification, often because the cells were damaged during slide preparation, so look for characteristic examples, and ignore the equivocal cells. Refer to the images in your texts and from the lecture and try to find an example of each leukocyte type using the 63x and 86x slides (there's less area to cover in these high-mag slides and the cells present are excellent, although the 63x slide does NOT contain any basophils).
The most common white blood cell is the neutrophil, which has a distinct multi-lobed nucleus (often 3-5 lobes). Also frequently seen are lymphocytes, which are small cells (often as small as RBCs) with a dark nucleus and very little cytoplasm. Another cell type is the monocyte, the largest of the blood cells. It has a large, relatively pale nucleus, and rather clear cytoplasm (granules are usually less apparent than those in the illustration in W). You will also see an occasional eosinophil, with prominent reddish granules filling the cytoplasm, and a nucleus with 2 (or sometimes 3) lobes. The exact color of the granules may vary from slide to slide, depending on how well the slide was prepared. In your particular slides they may be anywhere from bright red to dull brown. The remaining cell type you may see on your slides is the basophil, which is hard to find, since it constitutes less than 1% of the leukocytes (the 86x slide actually has THREE excellent examples). The cytoplasm contains large, irregular granules in a "grape-cluster" appearance that usually stain dark blue or almost black. Basophil nuclei may often appear somewhat oval-shaped, so, at first glance, they may be confused with lymphocytes. However, the presence of the large, dark-staining granules should help you distinguish them; also, remember that basophils are rare.
After you've done some looking on your own, here some quick links showing examples of each type of leukocyte (in order of their normal frequency in a blood smear):
CASE NUMBER 606, UMich slide 02S [DigitalScope] - courtesy of UMich
Clinical History: A 3-year-old boy presents with epistaxis and fever. Multiple cutaneous petechiae are evident, and there is generalized enlargement of lymph nodes, as well as palpable splenomegaly. The hemoglobin and platelet count are markedly decreased, and the white blood cell count is elevated to 40,000 cells/uL, with a preponderance of lymphoblasts. By flow cytometry, the neoplastic cells were CD19+/CD10+/CD34+. The peripheral blood film is shown.
Red cells show mild anisocytosis with slight hypochromia. The white cells are all blasts, about 2.5x the diameter of red cells which contain round, oval or slightly indented nuclei containing a fine uniform chromatin and 0-1 small nucleoli. There is a small amount of pale blue, agranular cytoplasm. Platelets are not seen.
Scan around the 63x and 86x slides at high magnification to see the various kinds of blood cells that were discussed in the lecture. Most abundant, of course, are the red blood cells (RBCs) or erythrocytes, which are seen in large numbers everywhere you look. In between the RBCs you should look for small, basophilic fragments which are platelets or thrombocytes [example] that are important in blood clotting. As you continue viewing, you will see occasional white blood cells (leukocytes). Some of the white blood cells may defy identification, often because the cells were damaged during slide preparation, so look for characteristic examples, and ignore the equivocal cells. Refer to the images in your texts and from the lecture and try to find an example of each leukocyte type using the 63x and 86x slides (there's less area to cover in these high-mag slides and the cells present are excellent, although the 63x slide does NOT contain any basophils).
The most common white blood cell is the neutrophil, which has a distinct multi-lobed nucleus (often 3-5 lobes). Also frequently seen are lymphocytes, which are small cells (often as small as RBCs) with a dark nucleus and very little cytoplasm. Another cell type is the monocyte, the largest of the blood cells. It has a large, relatively pale nucleus, and rather clear cytoplasm (granules are usually less apparent than those in the illustration in W). You will also see an occasional eosinophil, with prominent reddish granules filling the cytoplasm, and a nucleus with 2 (or sometimes 3) lobes. The exact color of the granules may vary from slide to slide, depending on how well the slide was prepared. In your particular slides they may be anywhere from bright red to dull brown. The remaining cell type you may see on your slides is the basophil, which is hard to find, since it constitutes less than 1% of the leukocytes (the 86x slide actually has THREE excellent examples). The cytoplasm contains large, irregular granules in a "grape-cluster" appearance that usually stain dark blue or almost black. Basophil nuclei may often appear somewhat oval-shaped, so, at first glance, they may be confused with lymphocytes. However, the presence of the large, dark-staining granules should help you distinguish them; also, remember that basophils are rare.
After you've done some looking on your own, here some quick links showing examples of each type of leukocyte (in order of their normal frequency in a blood smear):
I. Anemia Goal 1: Apply knowledge of nutritional biochemistry, erythropoiesis, and red blood cell structure and function to a discussion of the behavioral, hereditary, developmental, and chronic causes of anemia.
Objective 1: Iron-Deficiency Anemia
Explain the contribution of iron to red blood cell development and function; describe behaviors and conditions that lead to iron deficiency; and contrast the morphology and laboratory parameters of normal red cells versus iron-deficient cells.
Objective 2: Hereditary Spherocytosis.
Discuss the pathophysiology of hereditary spherocytosis.
Objective 3: Hepcidin Regulation, Iron Overload, and Anemia of Chronic Disease
Discuss the role of hepcidin as an iron regulator and describe how different types of alterations in the hepcidin pathway can produce anemia of chronic disease or iron overload.
Objective 4: B12 and Folate Deficiencies
Discuss the role of vitamin B12 and folic acid in red cell development and describe the pathophysiology of anemia arising from B12 and folic acid deficiency.
Objective 5: Anemias of Red-Cell Destruction
Explain the mechanisms by which anemia is produced on the basis of shortened red cell survival, distinguishing between intrinsic and extrinsic causes of red cell destruction.
Objective 6: Aplastic Anemia.
Compare and contrast congenital and acquired forms of aplastic anemia.
Objective 7: Hemoglobinopathies and Thalassemia
Describe the structural alterations and regulatory abnormalities associated with hemoglobinopathies and thalassemia, and discuss how these abnormalities give rise to the clinical manifestations of these diseases.
II. White Cell Disorders, Lymph Nodes, Spleen, and Thymus
Goal 1: Nonneoplastic Causes of Leukopenia and Leukophilia
Apply knowledge of anatomy and physiology to describe the conditions leading to increased or decreased numbers of white blood cells.
Objective 1: Leukocytosis
Define leukocytosis, describe several etiologies leading to it, and contrast it with leukemoid reaction.
Objective 2: Leukopenia
Compare and contrast the causes, mechanisms, and consequences of neutropenia and lymphopenia.
Objective 3: Leukophilia
Describe the common causes for neutrophilia, lymphocytosis, monocytosis, eosinophilia, and basophilia.
Goal 2: Genetic Mutations in Hematologic Malignancy
Apply knowledge of general concepts of neoplasia to explain how genetic mutations can produce hematologic malignancies and how the clinical behavior of different malignancies can be explained by different mutations.
Objective 1: Germline and Somatic Mutations in Hematologic Malignancy
Explain the difference between germline and somatic mutations; give examples and explain how each mutation contributes to the development of hematologic malignancies.
Objective 2: Translocations in Oncogenes
Compare and contrast, with examples, translocations that result in malignancy by activation of oncogenes with those that produce fusion proteins.
Objective 3: Cell Proliferation or Cell Death in Lymphomas
Explain with examples how dysregulation of cell proliferation or of cell death can give rise to lymphomas, and compare and contrast diseases arising by each mechanism with respect to morphologic appearance and clinical behavior.
Objective 4: Molecular Basis of Leukemia and Lymphoma
Describe how understanding the molecular pathogenesis of leukemia and lymphoma can suggest targets for therapeutic intervention and give examples of diseases currently treated by targeted therapy.
Goal 3: Classification of Leukemia and Lymphomas
Apply knowledge of hematopoiesis to discuss the pathophysiologic basis for the classification of leukemia and lymphomas.
Objective 1: Morphology of Acute Leukemia and Lymphoma
Describe the morphologic features that characterize typical cases of acute leukemia and lymphoma.
Objective 2: Myeloid Neoplasia
Compare and contrast myelodysplastic syndromes, myeloproliferative neoplasms, and acute myeloid leukemia with respect to morphologic appearance, clinical features, and underlying pathophysiology.
Objective 3: Categories of Lymphoma
Compare and contrast low-grade or indolent lymphomas and high-grade or aggressive lymphomas with respect to underlying pathophysiology, morphologic features and clinical behavior.
Objective 4: Morphology of Acute Versus Chronic Leukemia
Discuss the morphologic appearance of a blast and be able to distinguish acute myeloid leukemia from chronic myelogenous leukemia.
Objective 5: Morphology of Lymphomas
Describe the histologic appearance of typical cases of follicular lymphoma, diffuse large B-cell lymphoma, small lymphocytic lymphoma/ chronic lymphocytic leukemia, and Hodgkin lymphoma.
Objective 6: Hodgkin and Non-Hodgkin Lymphoma
Compare and contrast Hodgkin lymphoma with non-Hodgkin lymphomas with respect to age and clinical symptoms at presentation, sites and pattern of spread of disease, cell of origin, histologic appearance, and prognosis and response to therapy.
Objective 7: Multiple Myeloma
Describe the clinicopathologic features of multiple myeloma in terms of clinical presentation, laboratory findings, radiologic findings, histologic features, and prognosis.
Goal 4: Clinical Features of Hematolymphoid Neoplasms
Discuss the clinical manifestations of hematolymphoid neoplasms including age distribution of different tumors, presenting symptoms and signs, disease complications, natural history, and response to therapy.
Objective 4.1: Clinical Features of Bone Marrow Neoplasms
Identify the tumors of bone marrow most likely to present with anemia, leukopenia, or thrombocytopenia and discuss the presenting clinical features most likely to be associated with each.
Objective 4.2: Staging of Hematolymphoid Neoplasia
Define staging as it applies to lymphoma and give examples of different lymphomas in which staging has different clinical implications.
Objective 4.3: Extranodal Lymphoma
Identify lymphomas most likely to present in or involve extranodal sites such as the gastrointestinal tract, bone marrow, blood, skin, or central nervous system.
Goal 5: Thymus
Apply knowledge of the anatomy and function of the thymus to summarize how malignant transformation of epithelial and lymphoid cells lead to immune dysfunction.
Objective 5.1: Thymoma
Describe the clinicopathologic features of thymic neoplasms.
Goal 7: Spleen
Apply knowledge of the anatomy and function of the spleen to explain how developmental anomalies, immune, and metabolic disorders neoplasia lead to splenic dysfunction.
Objective 7.1: Splenomegaly
Describe the clinicopathologic features of neoplastic and nonneoplastic disorders leading to splenomegaly.
