(From Path, 28-30 Sept 2000, by Brian Buschman)
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Neutropenia is simply a decrease in neutrophils by either decreased production or increased degradation. Decreased production may be from suppression of myeloid stem cells or from increased destructions from things like disease, exposure to drugs and the like.
Agranulocytosis is a severe form of neutropenia where the neutropenia is caused by drugs. It leads to frequent infections and is seen with ulcerating lesions of the mouth and pharynx. In general you see s/s of bacterial or viral infections since the body has lost it’s ability to fight them with granulocytes.
You can see leukocytosis in problems like:
1) Neutrophilic leukocytosis which occurs in bacterial infections.
2) Eosinophilia is common with allergy (type I hypersensitivity).
3) Basophilia is rare but is seen in myeloproliferative disorders like chronic myelogenous leukemia.
4) Monocytosis is seen with chronic infection, collagen vascular disease and inflammatory bowel disease.
The morphology of leukocytosis may include:
1) The presence of dark/coarse looking toxic granules. They are azurophilic granules.
2) Dohle bodies which are blue patches representing dilated ER.
3) Cytoplasmic vacuoles.
Lymphadenitis are swollen or inflamed lymph nodes. It can be either acute nonspecific with have swollen, engorged nodes with large germinal centers or it may be chronic with one of three patterns:
1) Follicular hyperplasia which is a proliferation of B-cellsin the lymph node follicle. It shows a large germinal center with a dark zone of proliferating B-cells and a lighter outer zone of other B-cells and macrophages. These macrophages are called “tingible body macrophages” because they are phagocytotic macrophages. (Not that the name makes any sense to me.)
Follicular hyperplasia lymphadenitis has mitotic figures and is similar to follicular lymphomas.
2) Paracortical lymphoid hyperplasia is when you have T-cell proliferation. The activated T-cells are called immunoblasts and are 3-4 times the size of resting lymphocytes.
3) Sinus histocytosis or reticular hyperplasia is a nonspecific distention of the sinusoids. It is most often seen when the nodes are draining cancer.
Chronic lymphadenitis is usually a non-tender swelling that is seen in axillary and inguinal nodes.
There are three classes of white cell neoplasms which are based on cell type:
1) Lymphoid neoplasm (T-cell and/or B-cell neoplasm)
2) Myeloid neoplasm of erythrocytes, granulocytes or Thrombotic cells.
3) Proliferation of histiocytes.
There are three classes of lymphoid neoplasm that all have their characteristics:
1) Lymphocyte leukemia is a lymphoid neoplasm with bone marrow involvement, accompanied by tumor cells in the peripheral blood.
Lymphocytic leukemias have s/s that indicate bone marrow tumors that are suppressing hematopoiesis. The tumors also spread and infiltrate the spleen and liver leading to enlargement.
2) Lymphoma is a proliferating discrete mass. It may either be Hodgkin’s Disease (HD) or non-Hodgkin’s lymphoma (NHL). All HD and 2/3 of NHL present with non-tender nodal enlargements. The other 1/3 of NHL have enlargements of strange places like the stomach or skin. They are classified by the revised European-American classification of lymphoid leukemias.
3) The third type of lymphoid neoplasm are plasma cell neoplasms that are made of terminally differentiated B-cells that are made in the marrow and attack the bone locally.
Lymphoid neoplasms you need to examine then histologically to make the diagnosis. Clonal proliferation may be malignant. Most are of B-cell origin. It might be stating the obvious to say that immune abnormalities develop.
Usually tumors are disseminated by the time the diagnosis is made.
There are four lymphoid neoplasms that are usually seen in adults:
1) Follicular lymphoma (B-cell)
2) Diffuse large B-cell lymphoma.
3) Small lymphocyte lymphoma/chronic lymphocyte leukemia.
4) Multiple myeloma.
In children there are two classes of lymphoid neoplasms that you are most likely to see:
1) Acute lymphoblastic leukemia/lymphoma.
2) Burkitt lymphoma.
Chronic lymphocytic leukemia is effectively the same as SLL (small lymphocyte lymphoma). Both are peripheral B-cell neoplasms. CLL is the most common adult leukemia, especially in patients older then 60. SLL is a rare NHL.
Morphologically CLL involved the lymph nodes where you find proliferation centers making excess B-cell. The B-cell tends to be small with some larger precursor cells around it. You find fragile “smudge cells” in peripheral blood.
Clinically you will see generalized lymphadenopathy, hepatosplenomegaly and increased bacterial infections. You get increased infections because the B-cells are messed up so they do not produce the proper antibodies. You will see small lymphocytes peripherally with little cytoplasm.
Most patients survive 4-6 years with variable courses. More aggressive forms transform into Richter syndrome which is a B-cell lymphoma. It presents with a CD5 T-cell marker even though it is a B-cell leukemia.
Follicular lymphoma is the most common NHL. If is often a result of a t(14:18) that causes over expression of the bcl-2 protein. Morphologically you see nodular growth in lymph nodes with lots of small cleaved cells. Eventually bone marrow becomes involved.
Clinically patients, especially older ones, present with generalized lymphadenopathy. Survival is usually 7-9 years. 30-50% transform into diffuse large B-cell lymphoma. It shows CD10+5-.
Diffuse large B-cell lymphoma often starts as a growing mass at a single nodal site. It is an aggressive neoplasm with a male predominance. There are two types:
1) Body cavity large B-cell lymphoma such as what is seen with HIV when they develop diffuse large B-cell lymphoma. It begins as pleural or ascitic effusions. It is seen in cells infected with humanherpesvirus 8.
2) Immunodeficiency associated large B-cell lymphoma are associated with EBV. It arises in many T-cell immunodeficient states.
Morphologically you see large cells with a diffuse growth pattern. Large cells have large nucli that might be multiple nucli or multilobated.
Clinically it shows rapidly enlarging nodes. It first shows in the GI, skin, bone or brain. (Sites with exposed surfaces plus the brain.) It can involve the marrow.
Diffuse large B-cell lymphoma is caused by t(14;18) and B-cells show CD19 and CD20.
Multiple myeloma is a proliferation of plasma cells of unknown causes. It causes skeletal problems at multiple sites. Myeloma cells need IL-6 to survive so it is a bad sign when the patients present with high levels of IL-6.
Cytokines mediate bone destruction and many cells contain HHV 8 (humanherpesvirus 8). The skeleton suffers multifocal destruction. Pathologic fractures and x-ray “punched-out” are common. It is caused by osteoclast activation by plasma cells. Plasma cells are increased by ONLY CENTRALLY. The defects are filled with a soft, red, gelatinous tumor.
Plasma cells may appear normal or may present as:
1) Plasmablasts which have less condensed chromatin.
2) Mott cells with blue grapelike cytoplasmic droplets.
3) Russell bodies which are PAS positive inclusions in the cytoplasm.
4) Flame cells that have a fiery red cytoplasm.
Clinically they present “myeloma kidney” because of BJP damage. Most produce a monoclonal response usually IgG or IgG (not the usual IgM of monoclonal responses). Other signs include hyperviscosity, hypercalcemia, renal insufficiency and normocytic anemia.
Acute lymphoblastic leukemia/lymphoma is called lymphoblastic because of problems with B-cell/T-cell precursors. The lymphoblasts lack Ig and express TdT.
It may be associated with either t(9;22) or t(12:21). There is a poor prognosis with the t(9:22) form but a good one with the t(12:21) form. It is seem predominantly in kids and is usually overcome with chemo.
Three are three types of ALL. Burkett’s is one type to be discussed in the next section but the other two are:
1) Pre-B-cell tumors which are the predominant type. They have extensive marrow involvement and variable peripheral blood involvement. Pancytopenia may be seen.
2) Pre-T-cell tumors are less common and seen more as a lymphoma with thymic involvement.
It is important to differentiate between ALL and AML. In ALL it is lymphoblastic so you see scant agranular cytoplasm, lack of peroxidase granules and absent nucli. Problems with lymphoid cells. AML is based on myeloblasts so you see normal lymphocytes.
Clinical signs of ALL include rapid onset, fever, bleeding, lymphadenopathy, splenomegaly, hepatomegaly and BONE PAIN. (I think this is the first one so far with direct pain).
Burkitt lymphoma has a t(8;14) which moves the c-myc gene from chromosome 8. This causes a high mitotic rate. It is related to ALL but is a lymphoma of mature B-cells. Since they are mature they properly possess B-cell markers and surface IgM.
There is an African type BL which is endemic, a sporadic type that is non-endemic and a subset that is HIV related. All endemic (African BL) cases show EBV as do some of the HIV related cases but most sporadic cases do not.
LPL is a B-cell neoplasm of the elderly that secretes monoclonal IgM. As is characteristic of Waldenstrom’s macroglobulinemia there is a hyperviscosity. The name plasmacytic should give away it is a B-cell problem.
Their bone marrow will be infiltrated by lymphocytes, plasma cells and plasmacytoid lymphocytes. Like MM Russell bodies are usually seen (being red globules of immunoglobulin). You will usually not see bony erosions.
Clinically you see weakness, fatigue, weight loss, lymphadenopathy, hepatosplenomegaly, neurologic problems, VISUAL impairment.
It is INCURABLE. Prognosis is bad.
HD arises in a single node or chain and spreads. The characteristic which must be seen for diagnosis is Reed-Sternberg cells. RS cells are either B or T cells that have a double nucleus or a multilobed cell with a perinuclear halo. RS variants include the mononuclear , lacunar and histocytic types. RS cells show CD15 and CD30. CD45 is seen on 90% of malignant lymphoma.
HD also has a collection of normal inflammatory cells because of cytokines from RS cells like IL-4, IL-5 and TNF-a.
EBV is sometimes an etiological agent and there is a clear progression in HD from nodal to splenic, hepatic, marrow and on to extranodal.
1) Nodular sclerosis HD (65-75%) is seen more often in women. It has a good prognosis. It’s markers are CD15 and CD30 but it has abnormal RS cells. It also has collagen that binds and divides lymphocytes into nodules. Initially it starts in the parafollicular (T-cell) part of the LNs and spreads.
2) Mixed cellularity HD is the second most common form of HD and is seen mostly in males. They have classic RS cells (CD15, CD30). It is called mixed cellularity because it involves both lymphoid and myeloid cell infiltration (T-cell, plasma cells, eosinophils and macrophages).
3) Lymphocyte predominance HD is the least common form. It is distinguishable because it does not have classic RS and does not have CD15 or CD30. Rather it has CD20 and CD45. Note with CD45 it must be malignant. This, and only this, HD type can become a form of diffuse large cell lymphoma.
|
Nodular Sclerosis |
Mixed Cellularity |
Lymphocyte Predominant |
|
Female |
Male |
Male |
|
CD15, CD30 |
CD15, CD30 |
CD20, CD45 |
|
Abnormal RS cells |
Normal RS cells |
Abnormal RS cells |
|
|
|
May progress to diffuse large cell lymphoma. |
Differentiate it from ND by:
1) NHL have generalized peripheral LN involvement rather then starting at one spot.
2) Mesenteric nodes or Waldeyer’s ring (ring of tonsils) are usually involved.
3) Common in extranodal environments.
In general NHL presents with non-tender swollen nodes. Benign nodal hyperplasia will be tender.
There are three classes of myeloid neoplasms:
1) AML (acute myelogenous leukemia) which is an increase in immature myeloid cells in the marrow.
2) MDS (myelodysplastic syndromes) are associated with cytopenia and poor hematopoiesis.
3) MPD (chronic myeloproliferative disorders)
Acute myelogenous leukemia is an accumulation of immature myeloid cells in the marrow. It is broken into 8 categories M0-M7. M0-M3 are related to the degree of cell development. M4-M7 are related to specific myeloid cell types. See Stars table 12-16 on P. 288.
Clinically with acute myelogenous leukemia you will see fatigue, fever, mucosal and cutaneous bleeding and ecchymoses. DIC (disseminated IV coagulation) is seen due to procoagulants released (epically in M3). Infections by opportunistic organisms. CNS spread can be seen. Remember what will break when you have myeloid problems. Megakaryocytes (bleeding), erythrocytes (fatigue) and granulocytes (fever).
AML classically has Auer Rods which are abnormal azurophilic granules.
M0 are minimally differentiated myeloid cells. Since they are not differentiated yet they have no Auer rods.
M1 are myeloblasts that are not differentiated. They show a few Auer rods.
M2 have mature myeloblasts. It has Auer rods and are related to t(8;21)
M3 acute promyelocytic leukemia caused by t(15;17). M3 affects younger patients and has Auer rods. Patients develop DIC.
The retinoic acid receptor-a (RAR-a) is moved next to and fuses with the APL (acute promyelocytic leukemia) gene and causes relapse when the body metabolizes retinoic acid.
M4 – Acute myelomonocytic leukemia involves myocytes and monocytes. IT is similar to M2 but has no Auer rods.
M5 – Acute monocytes leukemia is in older patients and may be associated with either monoblasts or monocytes. High rates of lymphadenopathy. Monoblasts lack Auer rods. If it is peroxidase positive it has lobulated nucli.
M6 – Acute erythroleukemia
M7 – Acute megakaryocyte leukemia. Megakaryocyte predominance. Blasts react with platelet specific antibodies.
Remember that neoplasm has a higher rate of reproduction then cells.
Myelodysplastic syndrome is a failure of myeloid development (dysplastic). It effects all three myeloid lineages. It is likely to convert to AML. Clinically it will present as pancytopenia and you must R/O B12/Folate deficiency and ALL as possible causes. MDS is a disease of exclusion.
It can either be:
1) Idiopathic (primary MDS)
2) Secondary to radiation therapy.
There are four types of MPDs.
1) Chronic myelogenous leukemia (CML)
2) Polycythemia vera (PV)
3) Essential thrombocytosis
4) Myelofibrosis with myeloid metaplasia
CML is caused by the Philly chromosome t(9;22) where the abl gene is moved next to the bcr gene causing unnecessary tyrosine kinase activity. It can be detected by karyotyping, FISH or RT-PCR.
It has a morphology of “ sea-blue” histiocytes. Peripheral blood has high leukocytes, low myeloblasts, eosinophilia, basophilia and thrombocytosis. Splenomegaly and extra medullary hematopoiesis.
Clinical findings include nonspecific symptoms, detection of the bcr-abl gene fusion. Lack of leukocyte alkaline phosphatase.
It begins slowly and half enter an accelerated phase leading up to a blast crisis. Others go straight into a blast crisis. The blast crisis resembles acute leukemia with myeloblasts. Some show TdT and CD10 and CD19. They need a marrow transplantation.
PV is an increase in RBC production showing elevated Hct. There is also an increase in granulocytes of megakaryocytes. They proliferate a lot with very little EPO. Most other polycythemias are results of elevated EPO.
Morphology includes hypocellular BM especially with RBC progeny. There is also extramedullary RBC production in the spleen and liver. Therefore there is hepatosplenomegaly. Late in it’s course the stem cells can be “used up” and can be replaced by fibrotic tissue. PV can transform to AML.
Clinically you can see increased Hct, increased viscosity, abnormal blood flow, distension and stasis. Headache, dizziness and GI symptoms. Most patients are hypertensive. It is best treated with phlebotomy.
Essential thrombocytosis is associated with increased megakaryocytes and elevated platelets. It is a disease of exclusion because thrombocytosis is often seen in other leukemias.
Myelofibrosis is a disease where the myeloid stem cells undergo hyperplasia and are then replaced by fibrotic tissue. It is caused by PDGF and TGF-b activating fibroblasts.
You see teardrop RBCs. It has late stage splenomegaly, anemia and abnormal erythrocytes. It mostly effects the elderly.
LCH is proliferation of Langerhans cells. They have abundant cytoplasm and HX bodies (Birbeck granules) which have a tennis-racket appearance.
There are three etiologies:
1) Acute disseminated LCH.
2) Unifocal LCH.
3) Multifocal LCH.
Hairy cell leukemia is a B-cell leukemia with hair-like projections. It has TRAP (tartate-resistant acid phosphatase).
Clinically it presents splenomegaly without hepatomegaly. It also has abnormal mycobacterial infections.
Adult t-cell lymphoma/leukemia is a disease of CD4 (TH cells) of people infected with HTLV-1. It causes multilobulated nucli. HTLV-1 can cause CNS demyelination. For later HTLV-1 is a STD that is mostly confined to the Caribbean.
Mycosis fungoides is a TH-cell lymphoma originating in the skin. It has a cerebriform nucleus. It will spread to LNs and BM.
A type of MF (mycosis fungoides). It has an erythroderma and infiltration of BM and peripheral blood with tumor (Sezary) cells.
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