Heme Flashcards
Castleman Disease AKA angiofollicular hyperplasia.
Can be unicentric or multicentric. The unicentric type includes the hyaline vascular and plasma cell variants, while the multicentric type is mostly of the plasma cell type. 80% of cases are the hyaline vascular type, are M=F, any age. The multicentric type typically affects older patients, M slightly more than F, and is often seen in HIV patients and is associated with HHV-8.
Examples of pseudoneoplastic lesions in the lymphoreticular system and their related neoplastic mimes.
Selected lymphoid hyperplasias (lymphomas). Florid unilinear hyperplasia in bone marrow recovery (myelodysplasia; leukemia). Infection-related hemophagocytic syndrome (T-cell lymphoma). Epstein-Barr virus-related atypical lymphoid hyperplasias (large-cell lymphoma). Mycobacterial pseudotumors (dendritic-cell tumors).
Intravascular large B-cell lymphoma.
IVLBCL is a rare type DLBCL. Two forms have been described: classical, also known as Western form, with a cutaneous variant; and an Asian form occurring more frequently in the Far East. Intravascular lymphoma is most frequently a disease of B lymphocytes; although rare cases of T-cell and NK–cell disease have been reported, the WHO considers these cases to be a separate entity. M:F = 1.1:1, median age 67 years, range 41–85 years. By the time of presentation, most patients have advanced, disseminated disease. Patients may present with any of a myriad of symptoms, with any tissue potentially being infiltrated. CNS and cutaneous involvement is common, as is the presence of B symptoms. The WHO reports neoplastic cells will be found within the lumina of small and intermediate sized vessels, with prominent nucleoli, scant cytoplasm, and frequent mitotic figures. The cells inconsistently express several of the typical B-cell antigens, with CD19, CD20, CD79a, MUM1/IRF4, and Bcl-2 being the most commonly expressed. IVLBCL has no specific chromosomal alterations, but many abnormalities reported in other B-cell lymphomas may be seen in IVLBCL. The DDx includes lymphomatoid granulomatosis, primary CNS lymphoma, CD5+ diffuse large B-cell lymphoma, reactive lymphoid hyperplasia, CNS vasculitis, HPC-associated disorders other than IVLBCL, the acute leukemias, and lymphomas with an intravascular component.
How are clot sections prepared from bone marrow aspirates?
Clotted bone marrow left over from aspirate smears can be fixed in formalin with or without mercury chloride (B5) and then embedded in paraffin and stained with H&E.
Kikuchi-Fujimoto disease.
KFD, or histiocytic necrotizing lymphadenitis, is a self-limited condition, characterized by acute or subacute onset of benign painful lymphadenopathy with associated fevers and systemic symptoms. It MC affects females <40 yo and of Asian descent. Involved lymph nodes demonstrate circumscribed paracortical areas of apoptotic necrosis with abundant karyorrhectic debris and a proliferation of histiocytes, plasmacytoid dendritic cells, and CD8+ T cells in the absence of neutrophils. The etiology is unknown, although viruses and autoimmune mechanisms have been proposed. No specific laboratory tests contribute to the Dx. Dx requires histopathologic examination and exclusion of other factors by ancillary studies. Lymphoid malignancies, especially non-Hodgkin lymphoma; lymphadenopathy due to autoimmune disorders, primarily SLE; and infectious etiologies, such as EBV, HSV, Bartonella henslae, and toxoplasmosis should be r/o before the Dx of KFD, given the overlapping clinical and histologic features as well as the different therapeutic approaches. Tx involves supportive measures, and the symptoms usually resolve spontaneously within 4 months.
PIOLs?
Primary Intraocular Lymphomas. Is a subset of PCNSL. Is usually a DLBCL. They arise from the retina (a suggested renaming for PIOL is primary retinal lymphoma) and rarely from the uvea. Usually presents as a chronic intermediate uveitis unresponsive to corticosteroids in a median age in the 60s. The Dx is based on ID of atypical lymphoid cells in the eye, but b/c PIOL is a subset of PCNSL, the Dx can be made if the lymphoma cells are found in CSF, and an LP is less invasive than a diagnostic vitrectomy or a vitreous or aqueous aspiration anyway. The atypical lymphoid cells are usually large and pleomorphic, with scant basophilic cytoplasm and large nuclei. Other findings include hypersegmented, round, or clover-shaped nuclei with prominent nucleoli and rare mitoses.
The most common primary lymphoma subtype occuring in the ocular adnexa?
Low-grade, malignant, extranodal, marginal zone B-cell lymphoma of MALT type.
What are clonotypic B lymphocytes?
Clonotypic B lymphocytes (CBLs) are monoclonal B lymphocytes identified in patients with multiple myeloma, that share identical rearranged IGH-CDR3 sequences with the patient’s myeloma cells. CBLs are putative precursors of neoplastic plasma cells, and have been postulated to act as a therapy-resistant tumor reservoir that drives recurrence. CBLs show somatic mutations of IgH gene in a nonrandom fashion, without intraclonal variation, suggesting a postgerminal-center B-cell origin. Evidence, including oncogene expression, DNA aneuploidy, stem cell-like characteristics, and the clonal homogeneity, suggests that most of these B cells are malignant or premalignant and may represent precursors of neoplastic plasma cells. It is proposed that these B cells originate outside the marrow (lymph nodes and other lymphoid organs) and give rise to plasma cells only after migration to the bone marrow, which provides a microenvironment suitable for terminal plasma-cell differentiation. CBLs similar to those in MM are also detected in MGUS, although at a lower frequency.
What fixative and stain is used for bone marrow aspirate smears?
After the spread aspirate smears are allowed to air dry, they are fixed in methanol then stained with May-Grunwald-Giemsa or Wright stains.
What is the LAP score?
Alkaline phosphatase activity is found in the cytoplasm of neutrophils, osteoblasts, vascular endothelial cells, and some lymphocytes. The alk phos level of peripheral blood neutrophils is quantitated by the leukocyte alkaline phosphatase (LAP) score and is a useful screening test to differentiate chronic myelogenous leukemia from leukemoid reactions and other myeloproliferative disorders. The LAP score is usually performed using the Kaplow procedure. The LAP score is determined by evaluation of the staining intensity (ranging from 0 to 4+) of 100 counted neutrophils or bands. Normal LAP scores range from 15 to 130, but there may be variation in these ranges between laboratories. Entities with a low LAP score (130): Infections, growth factor therapy, myeloproliferative disorders other than CML, inflammatory disorders, pregnancy, oral contraceptives, stress, drugs (lithium, corticosteroids, estrogen). There is rapid loss of alk phos activity in samples drawn in EDTA anticoagulant. The test is optimally performed on fresh capillary blood fingerstick smears or on blood anticoagulated with heparin and should be performed within 48 hours after collection of the sample. The blood smears may be held in the freezer for 2-3 weeks with little loss of activity.
What is the MC cytogenetic abnormality in ALK positive ALCL?
t(2;5)(p23;q35). The t(2;5) fuses the ALK gene on 2p23 to the nucleophosmin (NPM) gene on 5q35, resulting in the constitutive activation of ALK kinase.
What stain is used for blood smears?
Romanowsky first used in 1890 a mixture of eosin and methylene blue. Subsequent modifications are May-Grunwald-Giemsa and Wright stains. Both contain eosin and methylene azures, which are derivatives of methylene blue.
ALL may primarily involve tissues, and when this is the primary manifestation, this process is called ___. AML may involve the tissues as well and when present is designated ___.
ALL may primarily involve tissues, and when this is the primary manifestation, this process is called lymphoblastic lymphoma. AML may involve the tissues as well and when present is designated myeloid sarcoma.
What is MPAL?
Mixed phenotype acute leukemia is a rare subset of acute leukemia, accounting for less than 5% of newly diagnosed cases, that includes both biphenotypic acute leukemia, in which markers of more than one lineage are expressed on a single blast population, and bilineal acute leukemia, in which two distinct blast populations of different lineages are present.
What are hematopoietic markers for identification of myeloblasts? Give patterns of CD34, TdT, CD10, c-kit, HLA-DR, sIg, and lineage specific markers.
CD34 +/-, TdT - (rarely + in M0), CD10 - (rarely +), c-kit +/-, HLA-DR +/-, sIg -. Lineage specific markers: CD13, CD33, CD15, CD11b, c-kit. CD34 and/or c-kit are typically present in AML, although some forms of AML may be entirely negative for CD34 and c-kit, notably AML with monocytic differentiation. Most AMLs express HLA-DR, but some myeloid leukemias (i.e. acute promyelocytic (M3) and AML with NPM1 mutations and cup-like nuclear invaginations) are HLA-DR negative. Myeloid sarcoma (chloroma) can be identified by immunostains for blast markers (CD34, c-kit), myeloid/monocytic markers (MPO, lysozyme) and CD43.
What are hematopoietic markers for identification of B-lymphoblasts? Give patterns of CD34, TdT, CD10, c-kit, HLA-DR, sIg, and lineage specific markers.
CD34 + (may be -), TdT +, CD10 + (occasionally -), c-kit -, HLA-DR + (rarely -), sIg - (or dim +). Lineage specific markers: CD19, CD79a, CD20 (+/-). DDx: Burkitt lymphoma has a mature B cell phenotype (sIg+, kappa or lambda +, CD20+, CD10+, Bcl-2 -) and is negative for blast markers (CD34, TdT).
What are hematopoietic markers for identification of T-lymphoblasts? Give patterns of CD34, TdT, CD10, c-kit, HLA-DR, sIg, and lineage specific markers.
CD34 +/-, TdT +, CD10 +/-, c-kit - (very rarely +), HLA-DR - (rarely +), sIg -. Lineage specific markers: CD3 (often cytoplasmic only).
All LGBCLs are positive for what hematopoietic markers?
CD45, pan-B markers CD19/20/22/79a and sIg.
What is typically seen on flow cytometry for CLL/SLL, MCL, FL, MZL, LPL, and HCL?
CLL/SLL: small FMC7- B-cells, light chain dim, CD20 dim. MCL: small FMC7+ B-cells, light chain bright, CD20 bright. FL: small-medium size light chain restricted CD10+ B-cells. MZL: often mixture of neoplastic and non-neoplastic B-cells; may be CD23+. LPL: light chain restricted small B-cells + plasma cells. HCL: CD20 bright, CD22 bright, CD103+, CD11c+, CD25+; very few monocytes in PB or BM.
WHO grading system for follicular lymphoma.
3 grades and 4 patterns. Grades are based on the number of centroblasts per HPF (40x objective; number should be based on the average of 10 fields). Grade 1 has 0-5 centroblasts per HPF. Grade 2 has 6-15 centroblasts per HPF. Grade 3 has >15, subdivided into 3A (residual centrocytes present) and 3B (centroblasts form solid sheets with no residual centrocytes). Patterns are based on the proportion of the follicular pattern. Follicular has >75% follicular pattern. Follicular and diffuse has 25-75% follicular pattern. Focally follicular/predominantly diffuse has <25% follicular pattern. Diffuse has 0% follicular pattern.
What are the diagnostic criteria for MGUS?
All three criteria must be met: 1. Serum monoclonal protein less than 3 g/dL. 2. Bone marrow plasma cells less than 10%. 3. Absence of end-organ damage and bone lytic lesions (end-organ damage=CRAB: hyperCalcemia, Renal insufficiency, normochromic normocytic Anemia, and/or Bone marrow lesions that can be attributed to the plasma cell proliferative disorder).
Diagnostic criteria for smoldering multiple myeloma.
Requires both: 1. Serum monoclonal protein (IgA or IgG) >3g/100mL and/or clonal bone marrow plasmacytosis > or = 10%. 2. Absence of end-organ damage or myeloma-related symptoms. (end-organ damage=CRAB: hyperCalcemia, Renal insufficiency, normochromic normocytic Anemia, and/or Bone marrow lesions that can be attributed to the plasma cell proliferative disorder).
Diagnostic criteria for multiple myeloma.
Requires all 3: 1. Clonal bone marrow plasmacytosis (typically >10%, but a minimal % is not designated in the setting of symptomatic myeloma). 2. Serum and/or urine M protein (except in patients with a non-secretory myeloma). 3. Evidence of end-organ damage, hyperviscosity, amyloidosis, or recurrent infections (end-organ damage=CRAB: hyperCalcemia, Renal insufficiency, normochromic normocytic Anemia, and/or Bone marrow lesions that can be attributed to the plasma cell proliferative disorder).
Diagnostic criteria for Waldenstrom’s macroglobulinemia.
Requires both: 1. IgM monoclonal gammopathy of any concentration. 2. Lymphoplasmacytic lymphoma with bone marrow involvement.
Monocytes develop in the bone marrow from myelomonocytic progenitor cells (CFU-GM) under the influence of the cytokines M-CSF and GM-CSF. Mature monocytes are released from the bone marrow into the circulation where they circulate with a half-life of ___ days before entering tissues and body fluids in response to inflammation and infection. Within tissues, monocytes may further differentiate into a variety of cell types (depending on the cytokine milieu), including ___. In body fluids, monocytes may differentiate into ___.
Monocytes develop in the bone marrow from myelomonocytic progenitor cells (CFU-GM) under the influence of the cytokines M-CSF and GM-CSF. Mature monocytes are released from the bone marrow into the circulation where they circulate with a half-life of 2 to 3 days before entering tissues and body fluids in response to inflammation and infection. Within tissues, monocytes may further differentiate into a variety of cell types (depending on the cytokine milieu), including macrophages, tissue histiocytes, dendritic cells, skin Langerhans cells, liver Kupffer cells, splenic macrophages, alveolar macrophages, multinucleated giant cells, CNS microglial cells, and bone osteoclasts. In body fluids, monocytes may differentiate into serous macrophages, type A synovial cells, and multinucleated giant cells.
What are Russell bodies?
Cytoplasmic plasma cell inclusions, representing aggregates of immunoglobulins synthesized by the cell. They are homogenous hyaline eosinophilic globules 4-5 micrometers in diameter. Can be seen in plasma cells in multiple myeloma or chronic inflammatory exudates.
Tidbits for determining B-cell and T-cell monoclonality.
Normal K:L is 2-3:1, but monoclonality should not even be considered until the ratio is at least 8-10:1. A reverse K:L in whish L>K is abnormal; be highly suspicious of monoclonality with a reverse K:L > 2:1. Normal CD4:CD8 is 2:1, but may be as high as 20-30:1 and still be considered nonspecific. T-cell monoclonality is suggested by loss of a pan-T-cell associated antigen, usually CD7 first, followed by CD5, CD2, and then CD3. Co-expression of both CD4 and CD8, or dual negative T-cells is aberrant, and suggests a lymphoproliferative process. Peripheral blood B-cell:T-cell lymphocyte ratio is ~1:4; lymph node B-cell:T-cell lymphocyte ratio is ~4:1.
What 3 surface antigens on flow are characteristic of NK cells?
CD16, CD56, CD57.
What 2 surface antigens on flow are characteristic of hairy cell leukemia?
CD11c and CD103.
What are the formulas for calculating MCV, MCHC, and Hct?
MCV = Hct x 1000 / RBC. MCHC = Hb / Hct x 100. Hct = MCV x RBC.
What are the formulas for calculating absolute reticulocyte count, corrected reticulocyte count, and reticulocyte production index?
ARC = % retics x RBC. CRC = % retics x Hct / 45. The CRC takes into account spuriously increased reticulocyte percentages due to a low Hct. RPI = CRC x 1 / correction factor. The RPI reflects the fact that in anemia, reticulocytes are released earlier from the marrow and therefore have a longer maturation time than normal to mature into red cells. The correction factor is 1.0 when the Hct is normal, 2.0 when Hct is 30, and 3.0 when Hct is 15.
Most commonly, hemoglobin is measured by the ___ method.
Most commonly, hemoglobin is measured by the cyanohemoglobin (hemiglobin cyanide) method, in which hemoglobin is converted to hemiglobin cyanide (HiCN), whose concentration is measured by spectrophotometry. To carry out this conversion, blood is dissolved in a solution of potassium ferricyanide and potassium cyanide which oxidizes the hemoglobin to hemiglobin (Hi; methemoglobin) and then converts it to hemiglobin cyanide (HiCN). The solutions’ absorbance at 540 nm reflects the amount of hemoglobin originally present. This methods detects all forms of hemoglobin (Hb, HbO2, Hi, HbCO) except sulfhemoglobin (SHb).
What are Quilty lesions?
QLs are collections of inflammatory cells usually found along the endocardium, but sometimes extending deeper into tissues, that can mimic acute rejection. QLs are also known as endocardial infiltrates and have been the subject of more than a dozen different studies, and there is still no consensus as to their etiology or significance. They have been associated with the use of cyclosporine and waxing and waning levels of immunosuppression. It has also been suggested that QLs represent a “benign” form of rejection, or an analogue of vascular rejection. More recent studies in experimental animals suggest that they may be sites of antigen processing and low grade immune stimulation. In human and experimental animals, QLs are comprised predominantly of T cells, with the CD4 subset predominating over CD8 cells by a ratio of 2-3:1. QLs have been subclassified on the basis of whether they infiltrate the underlying myocardium. In type A lesions, the border with the underlying myocardium is smooth. In type B lesions, the mononuclear cells infiltrate between myocytes in the underlying myocardium, but myocyte necrosis is not seen. On a practical level, QLs are generally not considered in the grading of cardiac allograft rejection, but mentioned in the diagnosis as a separate finding.
Membranoproliferative glomerulonephritis is a well-known manifestation of hepatitis ___. In the setting of malignancies, MPGN is often associated with ___, and is less common observed with solid tumors.
Membranoproliferative glomerulonephritis is a well-known manifestation of hepatitis C. In the setting of malignancies, MPGN is often associated with non-Hodgkin lymphoma, and is less common observed with solid tumors.
What do MCHC and MCH measure? When is MCH useful?
MCH is derived from the ratio of total hemoglobin expressed as g/L and the erythrocyte count expressed as x 10^12/L, the results are presented in picograms (10^-12 g). Therefore, MCH provides an absolute gravimetric measurement of the hemoglobin in the average erythrocyte. MCHC, however, provides the ratio of the hemoglobin to the volume of the average cell. MCHC is useful in many conditions, such as normochromic normocytic anemias, where the amount of hemoglobin produced parallels changes in the MCV. However, when evaluating conditions with a decreased eruthrocyte volume, such as thalassemia or iron deficiency, or increased absolute erythrocyte hemoglobin such as hemochromatosis, changes in erythrocyte volumes create problems in interpretation if the MCV or MCHC are used. For example, as erythocytes age, the MCV will increase and consequently the MCHC will decrease, yet the absolute amount of MCH does not change. Such constancy of the MCH is why decreased MCH is used as a tool for evaluating possible thalassemia, iron deficiency, or hemochromatosis.
What 3 patterns of spleen involvement can be seen with hematolymphoid processes?
In the majority of cases with hematolymphoid processes, the spleen will be involved in one of three patterns: predominately white pulp involvement, a predominately nodular pattern irrespective of white or red pulp, and predominately red pulp involvement. Most of the small B-cell lymphomas, including chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), follicular lymphoma, mantle cell lymphoma (MCL), splenic marginal zone lymphoma (SMZL), and lymphoplasmacytic lymphoma classically involve the white pulp with or without extension into the red pulp. Large cell lymphoma and Hodgkin lymphoma typically have a random, nodular pattern. Predominantly red pulp diseases include hairy cell leukemia (HCL), large granular lymphocytic leukemia, and myeloproliferative disorders, such as chronic myelogenous leukemia and chronic idiopathic myelofibrosis.
The plasma cell variant of Castleman’s disease comprises 10-20% of unicentric cases of Castleman’s disease and usually presents in the 6th decade of life. It is sometimes associated with system symptoms (fever, night sweats, and weight loss) and laboratory abnormalities, including increased serum ___ which is thought to originate from affected lymph nodes and be responsible for the systemic manifestations of the disease.
The plasma cell variant of Castleman’s disease comprises 10-20% of unicentric cases of Castleman’s disease and usually presents in the 6th decade of life. It is sometimes associated with system symptoms (fever, night sweats, and weight loss) and laboratory abnormalities, including increased serum IL-6 which is thought to originate from affected lymph nodes and be responsible for the systemic manifestations of the disease.
What are the histologic differences between HHV8-negative and HHV8-positive plasma cell variant cases of Castleman’s disease?
HHV8-negative plasma cell variant of CD is characterized by large sheets of mature plasma cells expanding interfollicular regions. While plasma cells are usually polyclonal, a subset of cases shows monoclonal plasma cells; these plasma cells are usually lambda light chain restricted. A subset of follicles may have hyaline vascular-like features; though, these features are often less distinct than in hyaline vascular CD. The HHV8-positive plasma cell variant of CD has interfollicular areas expanded by large sheets of mature, immature, and/or atypical plasma cells. These cases can have increased numbers of plasmablasts in the follicle mantle zones, and a subset of them evolves into HHV8-positive plasmablastic lymphoma.
Almost all cases of mantle cell lymphoma have a balanced chromosomal translocation between (genes and chromosomal locations).
Almost all cases of mantle cell lymphoma have a balanced chromosomal translocation between IgH and CCND1 (cyclin D1), t(11;14)(q13;q32).
Where is the most common extranodal site of lymphoma involvement?
GI tract.
Primary intestinal follicular lymphomas typically present in what specific location?
It typically presents in the second portion of the duodenum, and less frequently, in the jejunum. It appears endoscopically as one or more small polyps. Although typically asymptomatic, it may present with bowel obstruction. Staging must be performed to exclude GI involvement by a more widespread follicular lymphoma, such as one involving retroperitoneal lymph nodes. Patients with confirmed primary intestinal follicular lymphoma seem to have excellent survival and may not require treatment.
Plasmacytic differentiation is seen in what % of MALT lymphoma cases?
Plasmacytic differentiation in MALT lymphoma is fairly common, seen to some extent in ~1/3 of MALT lymphoma cases. Occasionally, plasma cells are the predominant cell type, potentially leading to confusion with other hematolymphoid neoplasms, such as plasmacytoma and lymphoplasmacytic lymphoma. Thus, MALT lymphoma with plasmacytic differentiation should be considered in the differential diagnosis of any plasmacytic lesion, particularly in the setting of a disease site or clinical senario that would be unusual for a plasmacytoma, such as a very young patient.
What is IPSID?
ImmunoProliferative Small Intestinal Disease is a rare disorder that is considered a variant of MALT lymphoma with nearly complete plasmacytic differentiation. Its name results from its preferential involvement of the small intestine, but it is also known as IgA heavy chain disease, because the neoplastic cells in about one-half of cases produce an abnormal, truncated IgA heavy chain that is missing the variable and the first constant regions and that can be found in the serum. The plasma cells will be positive for CD138 but negative for kappa and lambda light chains. IPSID is suspected to result from Campylobacter infection, and early cases have a relatively high rate of response to broad-spectrum antibiotics. Although it was thought that IPSID was entirely an inflammatory process, it has been now confirmed as a clonal process. It is relatively common for IPSID to progress to a high-grade lymphoma indistinguishable from DLBCL.
What is the classic morphologic appearance, immunophenotype, and cytogenetic abnormality seen in Burkitt lymphoma?
Morphologically, they consist of sheets of medium-sized transformed lymphocytes with minimal pleomorphism, multiple nucleoli, and numerous admixed tingible-body macrophages. Immunophenotypically, they are CD20-positive B-cells that co-express CD10, BCL6, and CD43. They are typically negative for BCL2. Ki-67 is nearly 100%. There are very few admixed T-cells. On cytogenetic studies, >90% of cases show a translocation involving the MYC gene on chromosome 8. Most cases have the MYC gene juxtaposed with the IGH gene on chromosome 14, while a minority involves the kappa (chromosome 2) and lambda (chromosome 22) light chain genes.
Nodular lymphoid hyperplasia in the lung.
Dense proliferations of lymphocytes in the lung, forming a mass lesion, should be ruled out for lymphoma. With this in mind, areas of lymphoid hyperplasia can form a localized or multinodular mass in lung. The inciting trigger for lymphoid hyperplasia has been proposed to be a foreign body/foreign antigen, and this can sometimes be demonstrated. These proliferations are composed of well formed follicles with organized B-cell and T-cell zones without invasion of pleura or bronchus. Involvement of epithelium can be present, mimicking a lymphoepithelial lesion, but in contrast to B-cell lymphoma, the infiltrating cells are T cells. The plasma cells within the lesion can have Russell bodies but not Dutcher bodies.
How is INR calculated?
INR = [Patient PT / Mean of normal PT range] ^ ISI. ISI = International Sensitivity Index for thromboplastin, used for PT determination. A patient with high ISI (ISI = ~2) will have low sensitivity to factor deficiencies. A patient with low ISI (ISI = ~1) will have high sensitivity to factor deficiencies.
What is peliosis?
The Greek word “pelios” means “discoloured by extravasated blood,” or “livid”. Peliosis is a pathological entity characterized by the gross appearance of multiple cyst-like, blood-filled cavities within parenchymatous organs. The classical pathoanatomical concept is based upon the opinion that peliosis exclusively develops in organs belonging to the mononuclear phagocytic system (liver, spleen, bone marrow, and lymph nodes). However, a paucity of studies indicates that other organs such as lungs, parathyroid glands, and kidneys may be affected too. Since the disease may culminate in spontaneous rupture of the affected organ and thus may mimic a violent death at autopsy, peliosis is far more than just another morphological curiosity.
What is peliosis hepatis?
Peliosis hepatis is characterised by randomly distributed multiple blood-filled cavities throughout the liver. The size of the cavities usually ranges between a few millimeters to 3 cm in diameter. The pathogenesis of peliosis hepatis is unknown. There are several hypotheses as to cause: it arises from sinusoidal epithelial damage, from increased sinusoidal pressure due to obstruction in blood outflow from the liver, or from hepatocellular necrosis. The condition is typically asymptomatic and is discovered following evaluation of abnormal liver function tests. However, when severe it can manifest as jaundice, hepatomegaly, liver failure and hemoperitoneum. Disease associations include… Infections: HIV, Bacillary peliosis (caused by Bartonella), Staphylococcus aureus. Chronic conditions: End stage renal failure, Kwashiorkor, tuberculosis and other chronic infections. Malignancy: Monoclonal gammopathies, Hodgkin disease, malignant histiocytosis, seminoma, hepatocellular adenoma, hepatocellular carcinoma. Renal transplants: It can be found in up to 20% patients, can be related to azathioprine or cyclosporine use, and may be associated with increased risk of transplant rejection. Drugs and toxins: Corticosteroids, androgens, azathioprine, tamoxifen.
What are nonmalignant medical conditions associated with reactive eosinophilia?
Allergic reactions (drug reactions, asthma), parasitic infections (strongyloidiasis), schistosomiasis, filariasis, toxocariasis), metabolic abnormalities (adrenal insufficiency), humoral immunodeficiency (hyperimmunoglobulin E syndrome (Job syndrome), Wiskott-Aldrich syndrome, hyperimmunoglobulin M syndrome, immunoglobulin A deficiency), pulmonary eosinophilias (eosinophilic granulomatosis with polyangiitis (formerly Churg-Strauss syndrome), allergic bronchopulmonary aspergillosis, chronic and acute idiopathic eosinophilic pneumonias), autoimmune blistering skin diseases (dermatitis herpetiformis, bullous pemphigoid).
Reactive eosinophilia is frequently observed in patients with lymphoma, often because of increased production of growth factors by the malignant cell population. In Hodgkin lymphoma, the reported incidence of blood eosinophilia is ___%. Bone marrow and tissue eosinophilia are also common, although surprisingly, there is no strong correlation with peripheral eosinophil counts. The incidence of tissue eosinophilia varies between types of Hodgkin lymphoma and is most common in the ___ form and the ___ form of the disease. As with many reactive eosinophilias, the mechanism appears dependent on increased ___ levels, and possibly IgE levels, both which may be produced directly by Reed-Sternberg cells.
Reactive eosinophilia is frequently observed in patients with lymphoma, often because of increased production of growth factors by the malignant cell population. In Hodgkin lymphoma, the reported incidence of blood eosinophilia is 15%. Bone marrow and tissue eosinophilia are also common, although surprisingly, there is no strong correlation with peripheral eosinophil counts. The incidence of tissue eosinophilia varies between types of Hodgkin lymphoma and is most common in the mixed cellularity form and the nodular sclerosing form of the disease. As with many reactive eosinophilias, the mechanism appears dependent on increased IL-5 levels, and possibly IgE levels, both which may be produced directly by Reed-Sternberg cells.
Eosinophilia may be associated with a variety of B-cell and T-cell neoplasms. B-cell lymphoblastic leukemia (BLL) with eosinophilia is one such example. It is often associated with a characteristic cytogenetic abnormality ___, which juxtaposes the IL3 gene on chromosome __ to the immunoglobulin heavy chain locus (IgH) on chromosome __. These cases are recognized in the 2008 WHO classification as B lymphoblastic leukemia with ___; IL3-IgH.” This rearrangement implies a “reactive” eosinophilia, in which increased IL-3 expression by malignant, lymphoblastic clones provides a paracrine signal, driving polyclonal expansion of the eosinophils.
Eosinophilia may be associated with a variety of B-cell and T-cell neoplasms. B-cell lymphoblastic leukemia (BLL) with eosinophilia is one such example. It is often associated with a characteristic cytogenetic abnormality t(5;14), which juxtaposes the IL3 gene on chromosome 5 to the immunoglobulin heavy chain locus (IgH) on chromosome 14. These cases are recognized in the 2008 WHO classification as B lymphoblastic leukemia with t(5;14); IL3-IgH.” This rearrangement implies a “reactive” eosinophilia, in which increased IL-3 expression by malignant, lymphoblastic clones provides a paracrine signal, driving polyclonal expansion of the eosinophils.
Myeloid sarcoma is also called…
Myeloid sarcoma is an extramedullary tumor mass of neoplastic immature myeloid (granulocytic or monocytic) cells, and is also called extramedullary myeloid tumor, granulocytic sarcoma, or chloroma.
Lymphangioleiomyomatosis. Locations? Association with a syndrome?
Lymphangioleiomyomatosis (or lymphangiomyomatosis) (LAM) occurs almost exclusively in reproductive age women and consists of a proliferation of immature myoid cells which are currently thought to derive from perivascular epitheliod cells (PEC). LAM may involve the lungs and axial thoraco-abdominal lymphatic system including both lymph nodes and the thoracic duct. Supraclavicular and inguinal nodes may rarely be involved. In most cases, the pulmonary manifestations dominate but LAM may occasionally present exclusively in the abdomen. Abdominal LAM may mimic ovarian carcinoma radiographically and patients may present with pain, often due to hemorrhage. LAM may occur in association with tuberous sclerosis (TS) or in isolation (sporadic LAM), although in either form the LAM cells may be associated with mutations of the TS genes, TSC-1 or TSC-2. Whether LAM is sporadic or associated with TS, the histologic appearance is the same but lymph node involvement is more frequent in patients without TS.
What two conditions are absolute contraindications for platelet transfusion, and what condition is a strong relative contraindication?
Absolute contraindications: TTP and HIT. Immune thrombocytopenia (idiopathic thrombocytopenic purpura and post-transfusion purpura) are strong relative contraindications; Do not transfuse unless severe thrombocytopenia with life-threatening bleeding; Large numbers of units may be needed due to rapid immune destruction.
Kimura lymphadenopathy epidemiology.
KL is a self-limiting non-neoplastic lymphadenopathy described originally in Asian countries (particularly China, Japan, and Indonesia) but also seen sporadically in Caucasians. KL presents classically in the head and neck region, involving deep soft tissues and local lymph nodes, predominantly of young adults. The age range is typically 27-40 and males are more often affected than females (3:1). No infectious agents have been demonstrated.
How can angiolymphoid hyperplasia with eosinophilia be distinguished from Kimura lymphadenopathy?
ALHE can have a striking histologic similarity to KL. ALHE is present mostly in Caucasians and can be confused with early stage KL. ALHE more often affects females and is seen in soft tissues and superficial dermis forming clusters of eosinophilic cells. ALHE typically presents as cutaneous papules rather than a mass lesion, and histology reveals non-nodal collections of eosinophils with hypertrophic endothelial cells that protrude and occlude vascular lumina in a tombstone pattern. Lymphadenopathy, which is an essential feature in KL, is not frequently seen in ALHE.
Mantle cell lymphoma represents between __% and __% of all non-Hodgkin lymphomas, and the tumor more commonly affects (male/female) patients, with most presenting with advanced disease, having bone marrow involvement at the time of diagnosis.
Mantle cell lymphoma represents between 2.5% and 10% of all non-Hodgkin lymphomas, and the tumor more commonly affects male patients, with most presenting with advanced disease, having bone marrow involvement at the time of diagnosis.
What FISH and IHC studies are useful in mantle cell lymphoma?
FISH studies for cyclin D1 are very important in making a definitive diagnosis of MCL. Translocation t(11;14)(q13;q32) is the chromosomal rearrangement juxtaposing the cyclin D1 gene locus (CCND1) on chromosome 11q13 with the immunoglobulin heavy chain locus (IGH) located on chromosome 14q32, placing CCND1 under control of IGH enhancer sequences, and leading to over-expression of cyclin D1 protein. In addition to cyclin D1 immunoreactivity, MCL tumor cells are positive for pan-B-cell markers, CD19 and CD20. Surface immunoglobulin and IgM are also positive, with or without associated IgD positivity. Tumor cells also show CD5 immunoreactivity, and are negative or only weakly positive for CD23, a marker helpful in distinguishing between chronic lymphocytic leukemia/small lymphocytic lymphoma, which is typically positive for CD23.
What are the two patterns of splenic follicular lymphoma?
The first pattern is characterized by an abnormal architecture composed of back-to-back follicles separated by scant red pulp. In the second pattern, the splenic architecture is relatively intact with scattered neoplastic follicles primarily involving the white pulp. This pattern must be discriminated from reactive follicular hyperplasia.
Are the lymphocytes seen in seminoma/dysgerminoma B-cells or T-cells?
T-cells.
___ is the most common primary pulmonary lymphoma, comprising up to 70% of all cases.
MALT lymphoma is the most common primary pulmonary lymphoma, comprising up to 70% of all cases. MALT lymphomas may have a deceptively heterogenous appearance microscopically, including germinal center formation and a mixture of T-cells and B-cells by IHC.
The primary entity in the differential diagnosis of pulmonary MALT lymphoma is ___.
The primary entity in the differential diagnosis of pulmonary MALT lymphoma is nodular lymphoid hyperplasia (NLH). Such lesions are extremely rare. The most important caveat is that any mass-forming lesion effacing the underlying lung architecture should be considered a lymphoma until proven otherwise, so careful exclusion of lymphoma is of paramount importance before rendering a diagnosis of NLH.
The primary entity in the differential diagnosis of pulmonary MALT lymphoma is nodular lymphoid hyperplasia (NLH). How do they differ histologically?
Typically, NLH presents as solitary peripheral nodules but may be multiple on occasion. NLH is well-circumscribed in comparison to MALT lymphoma, and lacks peripheral lymphangitic spread of the lymphoproliferative process. Additionally, lymphoepithelial lesions should be absent or very rare in NLH, and plaque-like infiltration of the pleura and Dutcher bodies should not be seen. Germinal center formation may be quite pronounced and plasma cells are prominent between the reactive follicles. Immunostains show a distribution of B- and T-cells typical of reactive follicles and the plasma cells lack light chain restriction. Similarly, no evidence of clonality should be evident by flow cytometry or molecular studies.
What is lymphomatoid granulomatosis (LYG)?
LYG is an angiocentric lymphoproliferative disorder which may involve multiple organs, but frequently involves the lungs. LYG is comprised of a mixture of neoplastic, large, morphologically atypical B-cells admixed with variable numbers of background T-cells. LYG is traditionally divided into three grades (LYG 1, 2, and 3) depending on the percentage of each cell type present, with LYG grade 3 being comprised essentially entirely of large B-cells and generally regarded as a B-cell lymphoma. Grade 1 LYG, however, is comprised primarily of small background T-cells and only a small percentage of large atypical B-cells, and therefore may be considered in the differential of MALT lymphoma. LYG occurs most commonly in immunocompromised individuals and typically presents as multiple masses, often with cavitation.
Histologic appearance of lymphomatoid granulomatosis (LYG).
Morphologically, LYG is angiocentric and may show large zones of necrosis with preservation of viable cells around blood vessels, although necrosis may not be as prevalent in cases of grade 1 LYG. While on initial evaluation the lesion may appear to be a mixture of T- and B- lymphocytes, careful inspection will reveal the atypical morphology of the B-cells. Additionally, LYG is an EBV driven process and the neoplastic B-cells will be positive for EBV latent membrane protein in most cases.
What virus does lymphomatoid granulomatosis have an association with?
EBV. LYG is an EBV driven process and the neoplastic B-cells will be positive for EBV latent membrane protein in most cases.
Histopathological diagnosis of myelolipoma involves demonstration of…
Histopathological diagnosis of myelolipoma involves demonstration of (a) lipomatous compartment, which is composed of mature adipocytes and (b) hematopoietic compartment, which includes any of the three lineages (myeloid, erythroid, and megakaryocytic). An exclusively lymphocytic, monocytic or histiocytic cell infiltration will not constitute the myeloid (marrow) compartment’s equivalence. In addition, caution should be exercised in tumors that show only mature myeloid cells (granulocytes, or eosinophils); granulocytic cells can be part of the inflammatory infiltrate within a lipoma, and do not constitute a true myeloid compartment. Similarly, immature myeloid cells, such as blasts, can be present in soft tissue involvement by leukemia (myeloid sarcoma), and hence should be interpreted with caution. Unequivocal proof of myeloid (marrow) compartment of myelolipoma is provided by the presence of erythroid colonies and/or megakaryocytic cells.
Benign lymphoepithelial cystic lesions in the salivary gland are seen in association with HIV infection. Describe.
Salivary gland enlargement associated with a significant lymphoid infiltrate is recognized in HIV-positive patients. Because the lymphoid tissue usually exhibits morphologic and immunophenotypic features similar to those seen in florid follicular hyperplasia and the lesions often occur in association with enlarged lymph nodes, benign lymphoepithelial cystic lesions are thought to represent a manifestation of persistent, generalized lymphadenopathy. AKA benign lymphoepithelial lesion, benign lymphocpithelial cyst, cystic lymphoid hyperplasia, and HIV-related salivary gland disease. The lesion most commonly arises in the parotid gland where it occurs in 3-6% of adults and 1-10% of children with HIV. Overall, benign lymphoepithelial cystic lesions account for ~25% of enlarged salivary glands in the HIV positive patient population. The lesions are often cystic, bilateral, multiple, and associated with lymphadenopathy. Morphologically, they are characterized by epithelial-lined cysts, often with squamous metaplasia, follicular hyperplasia, glandular atrophy, and in some cases epimyoepithelial islands. In many patients, treatment with HAART results in smaller lesions or their complete resolution.
The risk of developing lymphoma for patients with HIV-related multicentric Castleman Disease is ~__x higher than it is for the general HIV-positive patient population.
The risk of developing lymphoma for patients with HIV-related multicentric Castleman Disease is ~15x higher than it is for the general HIV-positive patient population. The survival of patients with HIV MCD who develop lymphoma is poor.
The incidence of non-Hodgkin lymphoma in HIV+ individuals is ~__ to __x greater than that of the general population.
The incidence of non-Hodgkin lymphoma in HIV+ individuals is ~70 to 80x greater than that of the general population.
Although not considered an AIDS-defining illness, HIV+ individuals have a __ to __x greater risk of developing cHL than immunocompetent patients.
Although not considered an AIDS-defining illness, HIV+ individuals have a 5 to 15x greater risk of developing cHL than immunocompetent patients. The incidence of HIV cHL has increased with the advent of HAART. Furthermore, the relative risk of developing cHL is higher in patients on HAART than it is in those who are not.
The HIV-related plasmablastic lymphomas characteristically arise in what location?
The HIV-related plasmablastic lymphomas characteristically arise in the oral cavity (60% of cases); however, they can also occur in other mucosal sites, such as the sinonasal cavity and the GI tract, and in nonmucosal sites, such as the skin, soft tissue, and lymph nodes.
What lymphoid proliferations are seen in association with HIV?
Progressive HIV-related lymphadenopathy/HIV-related benign lymphadenopathy. Benign lymphoepithelial cystic lesions. Multicentric Castleman disease. Lymphomas associated with HIV can be subcategorized as those occuring (1) also in immunocompetent patients (most cases), (2) more specifically in HIV+ patients (~5% of cases), and (3) in other immunodeficiency states (<5% of cases). The main entities in (1) are BL (~30% of HIV-related lymphomas), DLBCL (~40%), and cHL (~5-15%). These neoplastic entities account for most of the HIV-related lymphoma, although only the first 2 entities are AIDS-defining diseases. The neoplasms in (2) are highly associated with infection by EBV, KSHV/HHV8, or both. They include: Plasmablastic lymphoma. KSHV+/HHV8+ large B-cell lymphoma associated with MCD. Primary effusion lymphoma/Extracavitary primary effusion lymphoma. In (3), the HIV polymorphic lymphoid proliferations, which resemble the polymorphic poasttransplant-associated lymphoproliferative disorders seen in solid organ transplant recipients, comprise thie category of HIV-related lymphoma/lymphoma-like lymphoproliferative disorders.
Primary pulmonary lymphoma can be diagnosed when ___.
Primary pulmonary lymphoma can be diagnosed when there is a clonal lymphoid proliferation affecting one or both lungs (parenchyma and/or bronchi) without evidence of mediastinal lymphadenopathy or a mass on chest imaging in a patient with no previous extrathoracic involvement at the time of diagnosis or during the subsequent 3 months. Primary lymphoma of the lung is a rare disorder and represents only 0.3% of all primary pulmonary malignancies, <1% of all the cases of non-Hodgkin lymphoma, and 3-4% of all the extranodal manifestations of non-Hodgkin lymphoma.
What are the 2 main types of posttransplant lymphoproliferative disorder?
Polymorphic and monomorphic. Polymorphic PTLD is characterized morphologically by a plethora of monoclonal B cells in all stages of maturation as well as reactive T cells. Monomorphic PTLD is a subtype of non-Hodgkin lymphoma that appears as homogeneous sheets of transformed, monoclonal B cells, often with cytogenetic abnormalities. Regardless of the histologic features, the lymphoid cells in most cases of PTLD contain EBV detected by IHC or ISH.
What is pyothorax-associated lymphoma?
It is a rare EBV-positive DLBCL arising in patients with long-standing chronic pyothorax (treated with iatrogenic pneumothorax), secondary to tuberculosis. Patients present with a mass in the pleura accompanied rarely by lung mass or pleural effusion. On microscopic examination, the tumor shows diffuse proliferation of large atypical cells, with centroblastic and/or immunoblastic or plasmacytoid features with areas of necrosis. Neoplastic cells express pan-B-cell antigens and MUM1; rarely are CD138 positive; and are negative for CD10, bcl-6, and HHV-8. These patients have a dismal prognosis.
Isolated lymphopenia is uncommon but may be seen in what conditions (6)?
Isolated lymphopenia is uncommon but may be seen in SLE, HIV, SARS, anti-CD20 (rituxan) therapy, steroid therapy, and certain congenital immunodeficiencies (Bruton, SCID, DiGeorge, CVI).
With an isolated monocytopenia, consider what 2 conditions/situations?
With an isolated monocytopenia, consider hairy cell leukemia or steroid therapy. In patients undergoing chemotherapy, monocytopenia heralds the onset of neutropenia.
What are the 4 patterns of nonneoplastic lymph node proliferations?
Follicular pattern. Interfollicular pattern. Sinus pattern. Diffuse pattern.
How to differentiate reactive follicular hyperplasia from follicular lymphoma?
In RFH, the germinal centers usually remain separate and vary in size (but they may coalesce in some cases). The germinal centers contain numerous mitoses and tingible-body macrophages. Staining with bcl-2 is weak or absent within the germinal center (but strong in the surrounding mantle), while PCNA (Ki-67, proliferating cell nuclear antigen) is strongly expressed. In follicular lymphoma, follicles are often “naked” (mantles are obliterated) and confluent. Mitoses and tingible-body macrophages are rare. Staining with bcl-2 is strong in the follicle, and PCNA is weak.
What are some entities that cause a follicular pattern of hyperplasia (reactive follicular hyperplasia) in a lymph node?
Nonspecific reactive follicular hyperplasia (etiology unknown) is the most common scenario. HIV infection produces a profound variety called florid follicular hyperplasia. RA and Sjogren syndrome produce RFH, frequently with interfollicular plasmacytosis. Syphilis also produces a RFH with interfollicular plasmacytosis, but also causes capsular and trabecular thickening (due to chronicity) and capsular infiltration by plasma cells. Castleman disease.
What are some entities that cause an interfollicular pattern of nonneoplastic proliferation in a lymph node?
Viral infections such as infectious mononucleosis, CMV, and postvaccinial lymphadenitis. Hypersensitivity reactions, such as from dilantin. Kimura disease.
What are some entities that cause a sinus pattern of nonneoplastic proliferation in lymph node?
Sinus histiocytosis, a nonspecific reaction to numerous lymph node stimuli. Sinus histiocytosis with massive lymphadenopathy (Rosai-Dorfman disease). Lymphangiogram effect. Whipple disease. Hemophagocytic syndrome. Dermatopathic lymphadenitis.
What are some entities that cause a diffuse pattern of nonneoplastic proliferation in lymph node?
The diffuse pattern of nodal expansion, easy to confuse with lymphoma, is produced by several viruses, particularly EBV, but also CMV, HSV, measles, or post-vaccinia lymphadenitis.
What is the most common chromosomal anomaly in CLL/SLL?
Deletion of 13q14 (>50% of cases). Other frequent findings are trisomy 12 (15-20%), del(11q), del(14q), and del(17p).
What 3 patterns of bone marrow involvement may be seen in CLL/SLL?
Nodular, interstitial, and diffuse. The nodular and interstitial patterns correlate with a better prognosis, while diffuse a pattern correlates with a worse prognosis.
What are some atypical immunophenotypic features seen in CLL/SLL that correlate with atypical morphology, an unmutated IgVH gene, and a worse prognosis?
Bright CD20, bright sIg, CD38 expression, and ZAP-70 expression. ZAP-70 is the Z-chain-associated protein-70, a tyrosine kinase normally associated with the T-cell receptor (TCR) Z chain.
A subset of mantle cell lymphoma (MCL) with a tendency for peripheral blood involvement tend to have cytogenetic aberrations involving __, __, and __ (in addition to the requisite t(11;14)).
A subset of mantle cell lymphoma (MCL) with a tendency for peripheral blood involvement tend to have cytogenetic aberrations involving 8, 17, and 21 (in addition to the requisite t(11;14)).
What are the myc genes?
They are a family of retrovirus-associated DNA sequences (myc) originally isolated from an avian myelocytomatosis virus (myc for MYeloCytomatosis). The proto-oncogene myc (c-myc) codes for a nuclear protein which is involved in nucleic acid metabolism and in mediating the cellular response to growth factors. Truncation of the first exon, which appears to regulate c-myc expression, is crucial for tumorigenicity. The human c-myc gene is located at 8q24.
What is the most frequent CNS manifestation of Langerhans cell histiocytosis?
Central diabetes insipidus (DI) is the most frequent CNS manifestation of LCH, occurring in approximately 25% of pts. Multisystem LCH and craniofacial bone lesions with associated soft tissue masses are the 2 most important risk factors for the development of DI in patients with LCH.
What is Evans syndrome?
Evans syndrome is an autoimmune disease in which an individual’s antibodies attack their own RBCs and platelets. Both of these events may occur simultaneously or one may follow on from the other. Its overall pathology resembles a combination of autoimmune hemolytic anemia and ITP. The diagnosis is made upon blood tests to confirm not only hemolytic anemia and idiopathic thrombocytopenic purpura, but also a positive DAT and an absence of any known underlying etiology. Other antibodies may occur directed against neutrophils and lymphocytes, and “immunopancytopenia” has been suggested as a better term for this syndrome. Initial treatment is with glucocorticoid corticosteroids or IVIg, a procedure that is also used in ITP cases. Although the majority of cases initially respond well to treatment, relapses are not uncommon and immunosuppressive drugs are subsequently used. Splenectomy is effective in some cases, but relapses are not uncommon. The only prospect for a permanent cure is allogeneic HSCT.
Signet ring cells in the stomach. The differential diagnosis includes ___.
Lymphoma with artifactual signet ring cells due to cytoplasmic shrinkage (CD45 is usually positive in lymphoma). Metastases from breast or lung (clinical history, plus the use of appropriate immunostains such as TTF1 or GCDFP-15 is helpful). Reactive epithelial atypia associated with radiation treatment or chemotherapy. Xanthoma.
What histologic changes are seen for stress reactions in the thymus at 0-12 hours, 12-48 hours, 48-72 hours, 3-7 days, 7-14 days, and >14 days?
0-12 hours: Parenchymal hemorrhages. 12-48 hours: “Macrophages” (refers to the “starry sky” appearance in the cortex) in cortex. 48-72 hours: “Macrophages” with “mulberries” (refers to small clusters of lymphocytes) in cortex, cellularity of cortex begins to diminish. 3-7 days: Corticomedullary distinction lost with increasing prominence of Hassall corpuscles. 7-14 days: Involution begins whereby lymphocytes appear in increasing numbers in the medulla. >14 days: Advanced involution whereby there is overall relative depletion of lymphocytes and they mainly occupy the medulla.
Chronic myelogenous leukemia. Other names. Incidence. M:F. Age distribution.
Other names: chronic myeloid leukemia, chronic granulocytic leukemia. Incidence: 12.8 cases per 100,000 population per year, 15% of all adult leukemias. M:F=1.8:1. Age distribution: median age at diagnosis 46-53 yrs, occasionally seen in children.
Chronic myelogenous leukemia. Microscopic features in blood and marrow.
IN BLOOD: Leukocytosis composed of granulocytes of all stages of maturation. Myelocyte bulge, blasts usually less than 1% to 2%. Absolute basophilia in all cases, absolute eosinophilia in 80% of cases. Absolute monocytosis common, but monocytes less than 3% of leukocytes. Thrombocytosis common, can be prominent; thrombocytopenia very rare. IN MARROW: Hypercellular due to granulocytic and megakaryocytic proliferation. Myeloid : erythroid = 10 : 1 to 20 : 1. Widened paratrabecular cuff of immature granulocytes. Basophilia, blasts less than 10%. Small hypolobated (dwarf) megakaryocytes (not micro-megakaryocytes). Mild reticulin fibrosis. Pseudo–Gaucher histiocytes (in approximately 20% to 40% of cases).
Chronic myelogenous leukemia. What ancillary studies are done for blood and marrow.
FOR BLOOD: LAP (NAP) score low. B12 increased. FOR MARROW: Cytogenetic analysis: t(9;22) or variant (more than 95% of cases). Molecular: BCR-ABL1+ by FISH or PCR (100% of cases). Most cases: major BCR-ABL1, (e13 or14/a2 or 3), p210 protein. Rare cases: minor BCR-ABL1, (e1/a2 or 3), p190 protein. Rare cases: mu BCR-ABL1, (e19/a2 or 3), p230 protein.
Chronic myelogenous leukemia. What is in the differential diagnosis for chronic phase and for acclerated, blast phase?
Differential diagnosis for chronic phase: Leukemoid reaction. CMML. Atypical CML (Ph-neg, BCR-ABL1-neg). CNL. Other MPNs. Differential diagnosis for accelerated, blast phase: Ph+ ALL. MDS/MPN. AML.
Benign lymphoepithelial lesion.
AKA lymphoepithelial sialadenitis AKA myoepithelial sialadenitis. A reactive, focal to diffuse lymphoid infiltrate of salivary glands leading to parenchymal atrophy and degeneration of glandular elements into irregular epithelial complexes. Strong association with Sjogren syndrome; the majority of patients with SS also have BLEL of parotid glands, and are typically bilateral. BLEL occasionally seen independent of SS are usually unilateral and may be secondary to obstruction. Mean age 5th to 6th decade. M:F = 1:3. Potential evolution to extranodal marginal zone B-cell lymphoma.
Myoepithelioma of salivary gland. Micro. IHC. DDx.
Well circumscribed but variably encapsulated. Broad range of appearances due to multiple architectural patterns (solid, myxoid, reticular, nested, cord-like). Typically composed of spindled or plasmacytoid cells; may have dominant cell type or mixed morphology; plasmacytoid cells with hyperchromatic, round to oval nuclei and abundant, eccentric eosinophilic cytoplasm (characteristic but not pathognomonic, as also seen in pleomorphic adenoma of palate). Although not common, clear, polygonal (epithelioid), or stellate cells may be seen. Background with variable collagenization; may contain abundant acellular mucoid stroma. Lacks chondroid or myxochondroid matrix. Lacks infiltration, perineural invasion, profound pleomorphism, necrosis, increased mitotic figures. IHC: Reactive with pan-CK, CK7, CK14, p63, GFAP, and S100. Variable reactivity with actin-sm, actin-HHF-35, SMHC, and calponin (actins reactive in spindled cells but typically nonreactive in plasmacytoid cells). Mutations of p53 have been observed. DDx: pleomorphic adenoma, myoepithelial carcinoma, spindled soft tissue neoplasm, plasmacytoma.
What is a hemophilic pseudotumor?
A serious but rare (<2% incidence) lesion that occurs in the bones and deep soft tissues of patients with hemophilia, which can be confused with simple bone cyst, aneurysmal bone cyst, osteosarcoma, or angiosarcoma. Recurrent hemorrhages with reparative changes are responsible for the clinicopathologic manifestations. In bone, they may be intraosseous or sub-periosteal and usually develop in the femur, pelvis, and tibia in adults and the small bones of the hands in children. Histologically, areas of extensive hemorrhage, thrombus formation, bone destruction, and florid new bone formation characterize this lesion and, taken out of context, can be misinterpreted as malignant. Juxtacortical and intramuscular lesions exhibit central masses of organizing blood encased by a fibrous capsule that may be composed of 3 distinct layers: an inner hemosiderin-rich collagenous layer, a central layer of dense fibrous tissue, and an outer layer rich in elastin.
Flow cytometry is used to count and sort cells, as well as ___.
Flow cytometry is used to count and sort cells, as well as viral particles, DNA fragments, bacteria, and latex beads. Particles must be in suspension as single cells to be analyzed. If not, they can be made suitable for flow cytometry by the use of mechanical disruption or enzymatic digestion. Size restrictions also apply; cells or particles must be from 1–30 µm in diameter. Specialized flow cytometers are designed to handle smaller particles such as DNA fragments or bacteria.
What is a fluorescence-activated cell sorter?
FACS, an acronym for fluorescence-activated cell sorter, describes the ability of a flow cytometer to physically sort cells in a liquid suspension. To do so, the instrument design has to be modified to electrically charge cells of interest. This is done by first vibrating the sheath stream to break it into drops. The stream of drops flows past two charge (high-voltage) plates where cells of interest are electrically charged with a voltage pulse. Then the flow stream enters an electrical field where charged cells are deflected into suitable collection containers. Unwanted cells are not charged and are not deflected upon passing through the field.
Myelodysplastic syndrome.
Another less common condition but nonetheless an important cause of hypoproliferative normocytic anemia is MDS. This syndrome, which often presents as a normocytic anemia (although it can on occasion present as mildly macrocytic or as microcytic anemia), is refractory to treatment (e.g., transfusions of packed RBCs). It may present simply as a refractory anemia in its early stages and is thought to progress then to refractory anemia with ringed sideroblasts, and eventually to so-called preleukemic stages, in particular, refractory anemia with an excess of blasts (generally in the myeloid or lymphoid lines) and an excess of blasts in transformation. The condition may also present initially as a refractory cytopenia that involves all three (erythroid, granulocytic, megakaryocytic) hematopoietic cell lines. MDS appears to be a clonal stem cell disorder that is characterized by ineffective hematopoiesis.
What does it mean when a consistently low anion gap is seen?
Consistently low anion gaps, typically in the range of 1–3 mEq/L, signify the presence of high levels of basic protein, often a monoclonal paraprotein as occurs in plasma cell dyscrasias. Basic protein contains ammonium ions, the counter-ions for which are chloride. Now the “invisible” ion is ammonium, and a measurable increase in chloride ion occurs. This tends to decrease the anion gap. Persistently low anion gaps are a serious sign of possible malignancy (e.g., multiple myeloma).
What lymphoma can have cytoplasmic projections like hairy cell leukemia?
Similar to HCL, splenic marginal zone B-cell lymphoma has cytoplasmic projections when it involves peripheral blood. But in contrast to HCL with its circumferential fine projections, splenic marginal zone lymphoma is described to have ‘bi-polar’ cytoplasmic projections.
How is ALK IHC staining different in ALK-positive DLBCL and anaplastic large cell lymphomas?
ALK-positive DLBCL has a cytoplasmic granular staining pattern, while the majority of anaplastic large cell lymphomas have nuclear and cytoplasmic staining.
Brief overview of primary effusion lymphoma.
Primary effusion lymphoma is a large cell non-Hodgkin lymphoma localized predominantly in body cavities and occasionally in extracavitary regions. It presents with characteristic lymphomatous effusions in the absence of solid tumor masses, and pleural, peritoneal, and pericardial spaces are most often involved. It is typically associated with HHV-8 infection in immunocompromised individuals, in the setting of HIV infection, organ transplantation, or in rare cases advanced age. Histologically, PEL is characterized by atypical lymphoid cells of B-cell lineage with large nuclei and prominent nucleoli. Demonstration of HHV-8 latent antigens is required for diagnosis, and treatment modalities are limited at this time.
Epidemiology of primary effusion lymphoma.
The majority of cases occur in young to middle-aged males, either homosexual or bisexual, with HIV infection and severely immunocompromised. However, it can also occur in HIV-negative individuals who are immunocompromised as a result of solid-organ transplantation or cirrhosis. In rare instances, PEL can affect elderly individuals who are otherwise immunocompetent but live in geographic areas with high HHV8 prevalence, such as the Mediterranean region; these cases may be EBV negative.
What is extracavitary primary effusion lymphoma?
Primary effusion lymphoma is clinically unique in that it arises predominantly as a lymphomatous effusion within body cavities such as the pleural, pericardial, and peritoneal spaces, typically without any associated extracavitary masses. A subset of cases develop solid tumors in structures adjacent to the body cavity (eg, the pleura). Cases involving solid masses exhibiting morphology, immunophenotype, and gene expression profiles similar to classical PEL have also been described and subsequently labeled “extracavitary PEL.” Such extracavitary presentations more commonly involve the gastrointestinal tract. The most frequent causes of death in PEL patients, aside from progression of the lymphoma, are opportunistic infections and other HIV-related complications.
Molecular studies for primary effusion lymphoma.
Epstein-Barr virus infection can be demonstrated by in situ hybridization for EBV-encoded small RNA (EBER); immunohistochemical studies for EBV latent membrane protein 1 are negative. Molecular studies demonstrate clonal immunoglobulin gene rearrangements and somatic hypermutation, indicating that the cell of origin is a postgerminal center B cell. PCR can demonstrate presence of the viral genome. Cytogenetic studies have not demonstrated any recurrent chromosomal abnormalities.
IHC for primary effusion lymphoma.
Primary effusion lymphoma cells typically display a “null” lymphocyte phenotype: CD45 is expressed, but common pan–B-cell (CD19, CD20, CD79a, surface immunoglobulins) and T-cell (CD3, CD4, CD8) markers are absent. Instead, however, markers of lymphocyte activation (CD30, CD38, CD71, EMA, HLA–DR) and plasma cell differentiation (CD138) are often present. Bcl-6 is usually absent. Definitive diagnosis hinges on detection of viral infection by HHV8 in the neoplastic cells. IHC to detect expression of latency-associated nuclear antigen, LANA-1, are currently the standard assay to demonstrate evidence of infection; typically, positive results are characterized by a nuclear dotlike pattern. Epstein-Barr virus infection can be demonstrated by ISH for EBV-encoded small RNA (EBER); IHC studies for EBV latent membrane protein 1 are negative. Viral interleukin 6 is expressed by a variable subset of lymphoma cells, and IHC studies for this protein may be helpful for confirmation.
DDx of primary effusion lymphoma.
PEL has to be differentiated from other types of non-Hodgkin lymphoma by its morphologic features and unique immunophenotype. (HIV–positive individuals, for example, may have a Burkitt lymphoma with plasmacytoid differentiation, which can in rare cases present as a lymphomatous effusion.) Pyothorax-associated lymphoma. Plasmablastic lymphoma. Anaplastic large cell lymphoma. Plasma cell myeloma. Although each of these differential diagnoses shares morphologic features with PEL, each can also be distinguished from PEL by the absence of demonstrable HHV8 antigen within neoplastic cells.
What can cause additional reactivity on reverse typing of blood?
Extra antibodies. Transfusion (plasma components not type-specific to patient; IV Ig/albumin). Transplantation. Subgroup of a major blood type (especially subgroup of A (i.e. A2). Rouleaux (multiple myeloma; chronic inflammatory disorders).
What entities are in the differential diagnosis of an epithelioid GIST?
Poorly differentiated carcinoma. Melanoma/clear cell sarcoma. Glomus tumor. Gangliocytic paraganglioma. GI endocrine carcinoma. Extramedullary myeloid tumor. GI mucosal benign epithelioid nerve sheath tumor.
By what physiologic mechanisms does hydrops fetalis occur?
HDFN is the destruction of fetal or newborn RBCs by maternal alloantibodies specific for inherited paternal RBC antigen(s). The maternal IgG is transported across the placenta into the fetal circulation where it binds to the corresponding RBC antigen, targeting the antibody-coated RBCs for destruction by macrophages in the fetal spleen. The fetal marrow initially responds by increasing erythropoiesis and releases many of the newly produced RBCs into the circulation prematurely as nucleated precursors, leading to the term “erythroblastosis fetalis.” With worsening anemia, erythropoiesis expands to the liver and spleen, causing organ enlargement and portal hypertension. A resulting decrease in liver production of albumin leads to reduced plasma colloid osmotic pressure, generalized edema, ascites, and effusions known as “hydrops fetalis.”
What cell type(s) do HTLV-1 and HTLV-2 infect?
HTLV-1 predominantly infects CD4+ lymphocytes while HTLV-2 preferentially infects CD8+ lymphocytes (and, to a lesser extent, infects CD4+ lymphocytes, B lymphocytes and macrophages).
Do RBCs have HLA class I antigens?
The immature nucleated red cell also has class I antigens on its surface, but as the RBC matures the expression of class I antigens is diminished. Remnants of class I HLA antigens on red blood cells are also known as Bennet-Goodspeed (Bg) antigens. The antigens are listed with their corresponding class I HLA designation: Bga – HLA-B7, Bgb – HLA-B17, Bgc – HLA –A28.
On what cell types are HLA class II antigens expressed?
HLA class II antigens are selectively expressed by dendritic cells, macrophages, B-lymphocytes, and activated T-cells that function in antigen processing and self versus non-self recognition.
The i antigen from the I blood group system is normally present only in children. In what conditions/situations do adults have increased i antigen?
The iadult phenotype is a rare, autosomal recessive phenotype found in <1/10,000 donors. In Asia, the iadult phenotype can be associated with congenital cataracts. i antigen is also observed on cord RBCs and reticulocytes and in megaloblastic anemia, leukemia, and chronic hemolytic states as a sign of stressed erythropoiesis. Elevated i antigen is also observed in HEMPAS (hereditary erythroblastic multinuclearity with positive acidified-serum test), a congenital dyserythropoietic anemia.
Antibodies to the I blood group system. What Ig isotype? Auto and alloantibodies?
Anti-I and anti-i are antibodies of IgM isotype, reactive at room temperature. Autoantibodies to I are relatively common and are usually low-titered cold agglutinins. Some anti-I can have IH specificity, reacting stronger with group O and A2 RBC. Although generally benign, hemolysis secondary to high-titered anti-I is observed in cold autoimmune hemolytic anemia (CAIHA). CAIHA can occur in the setting of malignancy and occasionally infection (e.g., Mycoplasma pneumoniae). These antibodies display high thermal amplitude, often agglutinating RBCs at temperatures of 30°–34° C. In contrast, alloanti-I is relatively rare and is found as a naturally occurring antibody in iadult individuals.
Rouleaux formation or “pseudoagglutination.” In what conditions/situations is it seen and how do they cause the rouleaux formation?
Patients with multiple myeloma, Waldenström’s macroglobulinemia, and hyperviscosity syndromes have high concentrations of abnormal serum proteins that change the net surface charge on the RBC membrane. The cells thus cluster together in clumps that resemble macroscopic hemagglutination. Plasma expanders, such as dextran and hydroxyethyl starch, as well as some intravenous X-ray contrast materials can also cause rouleaux formation.
Patients with multiple myeloma, Waldenström’s macroglobulinemia, and hyperviscosity syndromes have high concentrations of abnormal serum proteins that change the net surface charge on the RBC membrane that can result in rouleaux formation or “pseudoagglutination”. How can the rouleaux formation be differentiated from true agglutination?
Rouleaux can be differentiated from true agglutination by direct microscopy (1) by the classical “stacked-coin” formation in rouleaux, and (2) by the loss of rouleaux after washing and resuspension in saline.
What are the physiologic processes that occur in cold agglutinin disease?
In vivo hemolysis is the result of binding of antibody to a patient’s RBCs in the peripheral vessels of the extremities, which are cooler (32° C and lower). As the cells recirculate to the body core and warm to 37° C, complement is activated and cells are destroyed. Hemolysis of cells may occur intravascularly but occurs more commonly via extravascular (C3b) pathways by macrophages in the reticuloendothelial system. Hemolysis may be chronic or episodic, depending on the thermal range of the antibody, and may be triggered by exposure to cold temperatures.
What are the 6 stages of maturation for granulocytes?
Myeloblast –> promyelocyte –> myelocyte –> metamyelocyte –> bands –> polymorphonuclear neutrophils.
The term “large granular lymphocytes (LGLs)” usually refers to NK cells, because up to __% of LGLs function as NK cells.
The term “large granular lymphocytes (LGLs)” usually refers to NK cells, because up to 75% of LGLs function as NK cells.
What clinical situations can leukoerythroblastosis be seen in?
Leukoerythroblastosis indicates severe disruption of the marrow by overwhelming infection, myelofibrosis, or bone marrow invasion by cancer, and may be associated with extramedullary hematopoiesis. A leukoerythroblastic reaction in infants can occur with severe hemolytic anemia (eg, erythroblastosis fetalis) or the rare bone disorder, osteopetrosis, in which failure of osteoclasts to resorb bone causes loss of hematopoietic marrow space and resultant extramedullary hematopoiesis.
What does the term “hyperleukocytosis” refer to?
Hyperleukocytosis refers to a WBC count greater than 100,000/mL, and is seen almost exclusively in leukemias and myeloproliferative disorders.
What is leukostasis?
Leukostasis, or sludging of WBC in small vessels of the brain, lungs, and kidneys, is an oncologic emergency that may cause life-threatening cerebral infarcts, cerebral hemorrhage, or pulmonary insufficiency caused by impaired blood flow. It is most common with acute myelogenous leukemia.
In which leukemia is leukostasis seen most commonly in?
Leukostasis is more common in acute myelogenous leukemia than in acute lymphoblastic leukemia, because myeloblasts are larger and more adhesive than lymphoblasts; it is rarely seen in chronic leukemias, even with extremely high WBC counts.
How does asplenia result in an increased WBC count? How does splenomegaly result in a relative lymphocytosis?
Because the normal spleen retains a large number of leukocytes, asplenia is associated with an increased WBC count. Splenomegaly may cause relative lymphocytosis as a result of splenic sequestration of granulocytes.
How do corticosteroids result in an increased WBC count?
Corticosteroids, which demarginate granulocytes, decrease neutrophil release from the marrow, and reduce neutrophil egress from the circulation, frequently cause leukocytosis.
Transient myeloproliferative disorder (TMD) is seen in up to __% of patients with Down syndrome (trisomy 21). TMD may also be seen in patients with trisomy 21 mosaicism who are phenotypically normal. TMD is characterized by peripheral blood leukocytosis in early infancy, and may include circulating myeloblasts in association with an accumulation of megakaryoblasts in the blood, liver, and marrow. TMD typically persists for several weeks and resolves spontaneously in most patients, but up to __% of affected patients later develop acute megakaryoblastic leukemia.
Transient myeloproliferative disorder (TMD) is seen in up to 10% of patients with Down syndrome (trisomy 21). TMD may also be seen in
patients with trisomy 21 mosaicism who are phenotypically normal. TMD is characterized by peripheral blood leukocytosis in early infancy, and may include circulating myeloblasts in association with an accumulation of megakaryoblasts in the blood, liver, and marrow. TMD typically persists for several weeks and resolves spontaneously in most patients, but up to 30% of affected patients later develop acute megakaryoblastic leukemia.
What are the WHO diagnostic criteria for systemic mastocytosis?
The diagnosis of SM requires the presence of either 1 major criterion and 1 minor criterion, or 3 minor criteria. Major criterion: Multifocal compact infiltrates of mast cells (>15) in extracutaneous organs. Minor criteria: 1. Presence of >25% atypical or spindle-shaped mast cells in extracutaneous organs. 2. Detection of KIT mutation D816V in extracutaneous organ(s). 3. Expression of CD2 or/and CD25 in extracutaneous mast cells (this is aberrant expression). 4. Serum tryptase concentration >20 ng/mL (with the exception of cases with associated clonal myeloid neoplsm).
Mastocytosis is recognized as a myeloproliferative neoplasm by the 2008 WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues and is defined as an accumulation of clonal mast cells in 1 or more organs. The skin is involved in most patients (80%) and may be the only organ involved. While the diagnosis of systemic mastocytosis depends on extracutaneous involvement, the skin can be involved as well. What is the most common extracutaneous organ involved?
Bone marrow. Other extracutaneous organs involved include liver, spleen, lymph nodes, and GI tract.
Are tryptase and CD117 (c-KIT) expressed in normal AND neoplastic mast cells?
Yes.
PAX-5 immunostain. What is it? What is it used for?
Also called BSAP, a B cell-lineage specific activator protein at 9q13. Member of paired box (PAX) family of transcription factors, which have a novel, highly conserved DNA-binding motif, known as the paired box; encodes BSAP expressed at early stages of B-cell differentiation, also in developing CNS and testis. Detected in B cells from pro-B cell stage to plasma cell stage where it is downregulated. Required for progression of B cell development beyond the early pro-B cell stage. Uses: Detection of pre-B cells (PAX5+, more sensitive and specific than CD20). Diagnosis of Reed-Sternberg cells in classic Hodgkin lymphoma (PAX5+) versus T / null cell anaplastic large cell lymphoma (PAX5-), although rarely positive in T cell lymphomas. Diagnosis of lymphoplasmacytic lymphoma / plasmacytoid differentiation in marginal zone lymphoma (PAX5+) versus plasmacytoma (PAX5-).
What are differences in the histologic appearance of nonneoplastic mast cells vs. neoplastic mast cells?
Nonneoplastic MCs have round to ovoid nuclei, abundant metachromatic or basophilic granules, and are generally individually dispersed in tisuse. Neoplastic MCs have atypical features such as elongated and spindled morphology and reduced or absent granularity. In addition, they often occur in clusters in tissue, and this in combination with their spindled morphology may lead to their misinterpretation as fibroblasts.
Activating somatic point mutations of the ___ gene are associated with mastocytosis and are encountered in most (>80%) of sporadic cases.
Activating somatic point mutations of the KIT gene are associated with mastocytosis and are encountered in most (>80%) of sporadic cases.
Sclerosing angiomatoid nodular transformation of the spleen. Overview.
Sclerosing Angiomatoid Nodular Transformation (SANT) of the spleen is a rare benign lesion of the spleen with unknown etiology. SANT is classically considered to be a female-predominant disease. Most lesions are found incidentally on imaging. Although SANT has specific imaging findings, the DDx from other splenic tumors or malignant lesions is very difficult. Histopathologically, these tumors reveal multiple confluent angiomatoid nodules; these nodules are surrounded by concentric collagen fibers exhibiting an inflammatory and myofibroblastic response and are accompanied by numerous erythrocytes and siderophages. The nodules are populated by endothelial cells, phenotypically recapitulating normal splenic vasculature, such as sinusoids, capillaries, and small veins. Nuclear atypia is minimal, mitotic figures are extremely rare, and necrosis is consistently absent. This lesion has a unique immunohistochemical profile characterized by CD34−CD31+CD8+ sinusoids, CD34+CD31+CD8− capillaries, and CD34−CD31+CD8− small veins. CD68 is positive in macrophages. Splenectomy is an effective technique for the management of SANT. Prognosis is good, with no recurrence after splenectomy.
What is the most common category of nonhematopoietic tumors seen in the spleen?
Vascular neoplasms are the most common primary nonhematopoietic tumors of the spleen. They include hemangiomas, littoral cell angiomas, splenic hamartomas (SHs), lymphangiomas, hemangioendotheliomas, angiosarcomas, and Sclerosing Angiomatoid Nodular Transformation (SANT).
What are the 3 most common sites to be involved by myeloid sarcoma?
Skin, bones, GI tract.
What are reticulated platelets?
Reticulated platelets (retPLTs) are platelets that are newly released from bone marrow megakaryocytes and still contain RNA. They have a short lifespan in the circulation and therefore reflect current megakaryopoietic activity, exactly comparable with reticulocytes and erythropoiesis. Reticulated platelets have clinical utility because they can help distinguish bone marrow failure from peripheral destruction in thrombocytopenia. Furthermore, retPLTs are an early predictor of bone marrow recovery after chemotherapy and transplantation.
What product is formed by t(9;22)(q34;q11.2) AKA Philadelphia chromosome?
It produces a BCR-ABL1 fusion with an abnormal tyrosine kinase activity that promotes the characteristic proliferation of progenitor cells in CML and ALL. BCR-ABL1 kinase signaling constitutively activates downstream proteins that promote growth factor-independent proliferation, altered adhesion, resistance to DNA repair, and inhibition of apoptosis that culminates in the malignant transformation of hematopoietic stem cells. The BCR-ABL1 fusion transcript and its resulting kinase have become a key target and biomarker in the treatment and monitoring of CML.
TdT (terminal deoxynucleotidyl transferase; also called terminal transferase), is a nuclear DNA polymerase in thymic and small number of bone marrow cortical lymphocytes. What cells are positive in normal and disease states, and what cells are negative?
Positive normal: Hematogones (B and T cell precursors) - coarsely granular or speckled pattern of TdT immunofluorescence, which often intensely aligns the nuclear membrane. Cortical thymocytes. Positive disease: B or T cell acute lymphoblastic leukemia/lymphoma - 95%, diffuse and strong, finely granular pattern of TdT immunofluorescence uniformly distributed in the nucleus. Indolent T cell proliferations. Thymoma (lymphocyte predominant). Acute myelogenous leukemia / myeloid sarcoma - variable, often weak and focal. Blastic plasmacytoid dendritic cell neoplasm - 60%. Merkel cell carcinoma - >50%. Negative: Myeloid cells; mature leukemias/lymphomas including Burkitt, diffuse large B cell, MALT, mantle cell, prolymphocytic leukemia (T cell), small cell lung carcinoma (usually); sarcomas.
Dx of polycythemia vera can be made when JAK2 V617F or exon 12 mutation is detected, along with increased hemoglobin and low or normal levels of erythropoietin. Clinically, what differences are seen in those with V617F mutation and in those with exon 12 mutation?
Clinically, patients with exon 12 mutations typically present with isolated erythrocytosis and suppressed erythropoietin, in contrast to the trilineage hyperplasia characteristic of patients with V617F mutation. Bone marrow from patients with exon 12 mutation often exhibits nonspecific morphology, with isolated erythroid proliferation and absence of prominent megakaryocyte atypia and clustering. Demonstration of exon 12 mutation in these patients is particularly helpful for ruling out reactive erythrocytosis.
What 2 mutually exclusive mutations are seen in virtually all cases of polycythemia vera?
JAK2 V617F (~96%) or JAK2 exon 12 mutations (~3%).
True or false. JAK2 and MPL mutations are completely specific for MPN.
False. Other hematological neoplasms (eg, myelodysplastic syndrome, chronic myelomonocytic leukemia, acute myeloid leukemia, and acute lymphoblastic leukemia) may harbor JAK2 and MPL mutations in low frequencies. Because JAK2 and MPL mutations are not completely specific for MPN, finding of these mutations in isolation does not warrant a diagnosis of MPN.
JAK2 gene. Chromosome? What does it encode? What happens with mutation?
The JAK2 gene maps to chromosome band 9p24 and encodes a tyrosine kinase protein composed of 1132 amino acids. It contains three critical domains: JH1, JH2, and four-point-one, ezrin, radixin, moesin (FERM) homolog domains. JAK2 protein kinase activity is activated by phosphorylation of its kinase domain. Activation of JAK2 induces signal transduction from both type 1 and type 2 cytokine receptors. Constitutive activation of JAK2 by either point mutation or fusion protein causes activation of the JAK/STAT pathway. The activated JAK2 causes phosphorylation of STATs, which then dimerize and translocate to the nucleus, where they regulate gene transcription. The constitutive tyrosine phosphorylation activity promotes cytokine hypersensitivity.
MPL (myeloproliferative leukemia virus oncogene) gene. Chromosome? What does it encode? What happens with mutation?
The MPL gene maps to chromosome band 1p34 and encodes the thrombopoietin receptor, which binds to thrombopoietin, the primary cytokine that regulates megakaryocyte development and platelet production, as well as hematopoietic stem cell homeostasis. Binding to thrombopoietin to MPL leads to activation of JAK2, which phosphorylates MPL and initiates a cascade of downstream signaling events that regulate cell survival, proliferation, and differentiation. The mutation W515L results in impaired function of the autoinhibitory region and subsequent ligand-independent thrombopoietin receptor activation. This then leads to subsequent activation of downstream tyrosine kinases and activation of transcription factors STAT3 and STAT5, which in turn leads to transformation of hematopoietic cells into cytokine-independent clones, resulting in megakaryocytic hyperplasia and marrow fibrosis. The mutation Y252H, which is located in the extracellular domain of MPL, confers hypersensitivity to thrombopoietin and increases the generation of megakaryocyte colonies in vitro and leads to increased thrombopoietin signaling and cell growth and survival.
What entities are in the DDx of small round cell tumors of the kidney?
The differential diagnosis of small round cell tumors of the kidney includes blastema-predominant Wilms tumors, lymphoblastic lymphoma, clear cell sarcoma, small cell carcinoma, monophasic synovial sarcoma, neuroblastoma, rhabdomyosarcoma, desmoplastic round cell tumor, rhabdoid tumor and extraskeletal Ewing sarcoma/PNET.
