Neoplastic Lymphoid Diseases

NEOPLASTIC LYMPHOID DISEASES Introduction o The bone marrow is the source of all cells in the blood, the two major lines of differentiation are lymphoid (which gives rise to B- and T-lymphocytes) and myeloid (which gives rise to neutrophils, eosinophils, basophils, monocytes, platelets and red blood cells) o All cells, whether myeloid or lymphoid, arise form a single cell called pluripotent stem cell. This cell undergoes a series of maturation and differentiation to finally give rise to the terminally differentiated cells in the peripheral blood. o Neoplastic diseases can be classified according to o Cell of origin (B-, T-, or myeloid) o Lymphoma or leukemia: lymphoma applies to tumor that causes enlargement of lymph nodes, while leukemia means neoplastic cells in the peripheral blood. Overlap occurs frequently. o Acute or chronic: acute means proliferation of immature early cells, while chronic means neoplastic proliferation of more differentiating cells, please keep in mind that the terms “acute” and “chronic” do not reflect the speed of which the disease or its clinical presentation develops. o The neoplastic disorders share chromosomal changes, translocations or mutations as driving forces behind the neoplastic transformation, several tumor have specific translocations (for example t(11;14) in mantle cell lymphoma), others have more complex changes. o These genetic mutations can result in arrest of maturation with uncontrolled proliferation as in acute leukemias in which cells do not mature and stay arrested in the immature phase while continue their uncontrolled proliferation. o On the other hand, some genetic changes promote proliferation without affecting maturation which gives rise to chronic leukemia, many of these neoplasms have genetic changes that result in autonomous tyrosine kinase activity (for example the BCR/ABL fusion gene in chronic myeloid leukemia). o Some genetic changes result in switching off apoptosis (remember apoptosis is a crucial mechanism that kills of unwanted cells). When apoptosis is switched off (by mutation or translocation), uncontrolled proliferation will ensue, resulting in neoplastic process, for example, in follicular lymphoma the antiapoptotic gene, BCL2, is activated continually by the gene IGH (see below for further discussion on FL) o Viruses can play a role in the pathogenesis of some tumors, examples: § EBV in diffuse large B-cell lymphoma, Hodgkin lymphoma, and Burkitt lymphoma § HTLV-1 in adult T-cell leukemia § HHV8 (human herpes virus 8) in the pathogenesis of Kaposi sarcoma, and primary effusion lymphoma. o Radiation, chemotherapy and smoking are also implicated in some tumors. LYMPHOIS NEOPLASMS. INTRODUCTION o These tumors are classified according to the cell of origin and the degree of maturation of the cells o The cell of origin cannot be determined by morphology alone and immunophenotyping should be performed on all tumors to detect the cell of origin § Immunophenotyping refers to the studies performed on the tissue (blood, bone marrow or lymph nodes) to detect certain proteins that reflect the cell of origin, these markers have specific expression on the cells, for example: • CD3 is a specific marker for T lymphocytes • MPO is a specific marker for myeloid cells • CD19 and pax5 are specific for B-lymphocytes. § TdT is a marker for immature B- and T- lymphocytes, it does not differentiate between B- and T-cell lymphoma but it is does differentiate between acute (in which TdT is positive) and chronic proliferations (in which TdT is negative) § CD34 is a universal marker for stem cells (or as we call them blasts) whether B-, T, or myeloid. CD34 is positive in acute leukemia but negative in more mature neoplasms. § CD10 is a marker for immature B cells as well as some mature B-cell neoplasms (see later). o The tumors are considered leukemias if they involve the peripheral blood predominantly, and lymphoma if they involve lymph nodes or other organs predominantly. § One exception is plasma cell myeloma, which is typically confined to the bone marrow with no lymph node or peripheral blood involvement. o Clonality: neoplastic proliferations are monoclonal while reactive conditions are polyclonal § Clonality can be detected in B neoplasms by assessing light chains (kappa and lambda), if the proliferation shows only kappa or only lambda, then it is monoclonal (and hence malignant) and if this proliferation shows both kappa and lambda then it is polyclonal, therfore benign. § For T-cell neoplasms, clonality can be detected by molecular studies for T-cell receptor rearrangement. o Tumors that will be discussed in this manuscript § Precursor B and T cell lymphoblastic lymphoma/leukemia— commonly called acute lymphoblastic leukemia (ALL) § Chronic lymphocytic leukemia/small lymphocytic lymphoma § Follicular lymphoma § Mantle cell lymphoma § Diffuse large B cell lymphomas § Burkitt lymphoma § Plasma cell myeloma and related plasma cell tumors § Hodgkin lymphoma § Marginal zone lymphoma of the mucosa associated lymphoid tissue (MALToma). § Hairy cell leukemia. § Mycosis fungoides Precursor B and T cell lymphoblastic lymphoma/leukemia— commonly called acute lymphoblastic leukemia (ALL) o Definition: neoplastic proliferations of immature B- or T- lymphocytes o Since both can present as leukemia or lymphoma, these entities were lumped into one entity carrying the designation “lymphoma/leukemia” since prognosis and treatment are the same. o Epidemiology: they are the most common cancers in children o 85% are B-cell lymphoblastic leukemia o 15% are T-cell lymphoblastic leukemia § B-ALL presents in children less than 5 years of age while T-ALL typically affects adolescents. (Keep in mind that tumor do not follow rules and this diagnosis can be made in all ages!) o Clinical presentation: o B-ALL is more likely to present as leukemia, presentation reflects bone marrow failure where the patient typically presents with fatigue and pallor (due to anemia), fever and infections (due to neutropenia) and bleeding (due to thrombocytopenia). o T-ALL is likely to present as a lymphoma and the clinical presentation is that of a mass effect (mediastinal mass resulting in shortness of breath for example) o CNS manifestations can occur as these tumors have tendency to infiltrate the CSF. o Diagnosis: Clinical presentation alone is not enough, and pathologic examination of the tissue with immunophenotyping is a must for diagnosis o Bone marrow and tissue: hypercellular with the normal cellular elements being replaced by sheets of immature cells with scant cytoplasm, round to oval nuclei showing fine chromatin and variably prominent nucleoli. o Immunophenotyping (performed by immunohistochemistry on tissue and/or by flow cytometry on peripheral blood or bone marrow aspirates) shows immature markers (CD34 and TdT) in both T-ALL and B-ALL. § B-ALL is typically positive for B cell markers such as CD19, pax5, CD20, CD22 and CD79. Also, B-ALL is positive for CD10. § T-ALL is typically positive for CD3. Note in the images the presence of lymphoblasts with scant cytoplasm, oval to round nuclei with fine chromatin (notice how similar they are to mature normal lymphocyte, and hence immunophenotyping is a must for diagnosis as morphology alone is not sufficient for diagnosis. Note also the absence of normal bone marrow elements (other cells that are normally present). The lower left image is a flow cytometry graph that shows these cells to be positive for TdT (which means that they are immature lymphoblasts) and CD10 (which means they are immature B lymphoblasts) and CD22 and CD19 (reflecting their B cell origin); diagnosis is Bacute lymphoblastic leukemia. o Prognosis: Generally, ALL has an excellent prognosis; with aggressive chemotherapy cure rates of ~80% can be attained. Generally speaking, B-ALL has a better prognosis than T-ALL. o Factors associated with good prognosis § Age between 2-10 years. § Low WBC count (less than 100,000/microliter) § Hyperdiploidy § t(12;21) o Factors associated with poor prognosis § Age less than 2 or more than 10 § High WBC count (more than 100,000/microliter) § Hypodiploidy or normal ploidy. § t(9;22) Chronic lymphocytic leukemia/small lymphocytic lymphoma o Definition: malignant proliferation of small mature B-lymphocytes that involves peripheral blood, lymph nodes or both o If the peripheral blood count of the neoplastic cells is more than 5000/microliter it is chronic lymphocytic leukemia (CLL). o If the neoplastic cells are less than 5000 with tissue involvement, it is called small lymphocytic lymphoma (SLL). o If there is no tissue involvement and the peripheral blood count is less than 5000, it is called monoclonal B-cell lymphocytosis-CLL type. o Epidemiology: it is the most common leukemia in adults. Typically affects elderly people. o Clinical presentation: o Often asymptomatic, the patient discovers lymphocytosis on routine blood tests performed for other purposes. o Nonspecific symptoms of fatigue, anorexia and weight loss o Mass effect: lymphadenopathy and hepatosplenomegaly. o Hemolytic anemia: For uncertain reasons. CLL causes derangement of the immune function with resulting autoantibodies against RBCs. o Diagnosis: o Peripheral blood, tissue and bone marrow reveal the presence of infiltration by small, mature lymphocytes with scant cytoplasm and clumped chromatin reminiscent of soccer ball (in contrast to the fine chromatin seen in ALL). o Immunophenotype: the tumor cells are typically monoclonal (expressing only kappa or only lambda) with expression of B-cell markers such as CD19, CD20, CD22, CD79 and pax5 § This tumor also expresses CD5 (normally positive only in Tcells, but remember this is a malignant tumor that does not follow rules). CD5 positivity is valuable in making the diagnosis § The other CD5 positive B-cell neoplasm is mantle cell lymphoma. Mantle cell lymphoma is positive for cyclin D1 while CLL is negative. (Needless to say, most T-cell tumors are positive for CD5!) o Note in the 1st image the complete effacement of the lymph node structure with sheets of neoplastic cells, in the 2nd image, the cells are relatively small with clumped chromatin and several small nucleoli that look like a football (soccer ball according to Americans!). Some cells have large nucleoli (arrow); these are called paraimmunoblasts. o Prognosis: o Generally, CLL is considered indolent but incurable, overall survival is 4-6 years but some patients survive more than 10 years with gentle chemotherapy. § Bone marrow transplantation is offered to young patients o In a small percentage of patients, transformation into a more aggressive neoplasm (typically diffuse large B-cell lymphoma) occurs with very poor prognosis. In this case survival is less than 1 year. Follicular lymphoma o Definition: a malignant neoplasm of mature B-lymphocytes that resemble Bcells in the follicle of the lymph node. Bone marrow and peripheral blood are frequently involved as well. o Epidemiology: Typically affects middle-aged to elderly population. o Much more common in the USA compared to Jordan. o Clinical presentation: generalized lymphadenopathy as well as nonspecific symptoms of weight loss, loss of appetite and fatigue. o Pathophysiology: FL is a tumor that is characterized by a specific genetic translocation t(14;18). This translocation juxtaposes the gene BCL2 on chromosome 18 with the continually active IGH (immunoglobulin heavy chain) on chromosome 14. This results in continuous activation of BCL2 which functions as an antiapoptotic gene resulting in uncontrolled proliferation of B-lymphocytes. o Diagnosis: lymph nodes are effaced by a neoplastic proliferation of B-cells arranged in follicles, the follicles have two populations of neoplastic cells: small cleaved lymphocytes with dense chromatin (centrocytes) and large cells with fine chromatin and prominent nucleoli (centroblasts). Must be differentiated from reactive lymphoid hyperplasia (see previous discussion). o Immunophenotype: the cells are monoclonal with expression of B-cell markers. Additionally, CD10 is positive and BCL2 is positive. § Remember that CD10 is also seen B-ALL, Burkitt lymphoma and some cases of diffuse large B-cell lymphoma. o Note in the image the presence of variably sized follicles that completely efface the normal lymph node architecture. The cells are composed of two cell types; centrocytes and centroblasts. o Prognosis: indolent but incurable tumor with median survival of 7-9 years o Transformation into more aggressive tumors (diffuse large B-cell lymphoma or Burkitt lymphoma) can occur in 30-50% of patients with dismal prognosis, survival is less than 1 year. Mantle cell lymphoma (MCL) o Definition: MCL is a B-cell neoplasm that recapitulates B-cells in the normal mantle zone of the lymphoid follicle. o Epidemiology: relatively uncommon tumor representing less than 5% of all lymphomas o Clinical presentation: generalized lymphadenopathy, abdominal heaviness secondary to splenomegaly which develops in ~50% of the patients. Sometimes mantle cell lymphoma presents as intestinal polyps noted on colonoscopy. o Pathogenesis: MCL is a tumor that has a specific genetic translocation; t(11;14) which juxtaposes the gene cyclin D1 on chromosome 11 with the IGH gene on chromosome 14 (same gene involved in follicular lymphoma and some other B-cell neoplasms). This results in continuous activation of cyclin D1 which functions to promote the G1-to S- phase progression during the cell cycle. o Diagnosis: The lymph nodes are replaced by sheets that have diffuse, or vaguely nodular, architecture. The cells are small to medium size with round to irregular nuclei showing clumped chromatin and variably prominent nucleoli (not that the morphology is similar to that of CLL and sometimes FL, therefore immunophenotyping is crucial for diagnosis). o Immunophenotype: the tumor expresses B cell markers and shows clonality with expression of kappa or lambda only (not both). § CD 5 is positive (remember the other tumor that is positive for CD5 is CLL). § Cyclin D1 is diffusely positive. § Note the small to medium size cells, this morphology is not specific and can be seen in many other B-cell neoplasms, immunophenotype is vital. o Prognosis: this is an aggressive tumor with 4-6 years median survival and treatment failure to conventional chemotherapy is the rule, bone marrow transplantation and some newer therapies carry some promise, but more studies are needed. Diffuse large B-cell lymphoma (DLBCL) o Definition: A B-cell neoplasm characterized by large cells (the word “large” in this context means three time larger than a normal lymphocyte) arranged in diffuse sheets. o Epidemiology: it is the most common lymphoma; typically affecting people at a median age of 60 years, but please keep in mind that any age can be affected. o Remember that the most common leukemia is CLL, the most common leukemia in children is B-ALL and the most common lymphoma is DLBCL. o Clinical features: Rapidly enlarging lymph nodes with frequent nonspecific general symptoms such as weight loss, fever and loss of appetite. Hepatosplenomegaly is common. o Diagnosis: The lymph node is effaced by sheets of large cells with fine chromatin and prominent nucleoli. o Immunophenotype: B-cell markers are expressed in addition to monoclonality. § CD10 is also expressed in a subset of DLBCL (remember that FL, Burkitt lymphoma and B-ALL also express CD10. Note the presence of large cells that show fine chromatin with prominent nucleoli. o Prognosis: DLBCL is an aggressive tumor that is rapidly fatal if left untreated, however, with proper treatment, cure can be achieved in 50% of patients. Burkitt lymphoma o Definition: a highly aggressive and rapidly proliferating tumor of B-cells of the germinal center. It is divided into two groups: sporadic and endemic. o Epidemiology: both tumors affect children and young adults. o Clinical features: The sporadic subtype presents as an abdominal mass while the endemic subtype presents commonly as a mandibular mass. o Pathogenesis: Almost all cases of BL have a translocation involving the gene MYC on chromosome 8. The translocation can be with IGH (t(8;14))on chromosome 14, kappa on chromosome 2 (t(2;8))or lambda on chromosome 22 (t(8;22)). The net result of all these translocation is the upregulation of the gene MYC which promotes cell growth and proliferation, BL is believed to the fastest growing tumors in humans. o In endemic subtype infection with EBV is present in almost all cases. o Diagnosis: the tissue is infiltrated by diffuse sheets of intermediate cells that have moderate cytoplasm, fine chromatin and variably prominent nucleoli. The tumor exhibits a high mitotic index and contains numerous apoptotic cells, the nuclear remnants of which are phagocytized by interspersed benign macrophages. These phagocytes have abundant clear cytoplasm, creating a characteristic “starry sky” pattern. o Immunophenotype: B-cell markers are expressed with monoclonality. o CD10 is positive. o BCL2 is characteristically negative. o Note in the image the presence of diffuse sheets of neoplastic cells, also note the starry sky appearance (the macrophages with their clear cytoplasm look like shining stars in a sea of darkness created by the neoplastic B-cells. Note the frequent mitotic figures in the image (arrows) o Prognosis: a very aggressive and rapidly fatal tumor if left untreated, however, with treatment most patients are cured. Plasma cell myeloma (PCM) o Definition: A B-cell neoplasm of terminally differentiating antibodyproducing plasma cells. o Epidemiology: the tumor typically affects elderly people. o Clinical features: PCM is associated with nonspecific symptoms such as fever, weakness and loss of appetite. Additionally: o Lytic bone lesions resulting in bone pain and pathologic fractures o Anemia secondary to tumor infiltration of the bone marrow. o Renal dysfunction o Hypercalcemia due to bone destruction o PCM is usually confined to the bone marrow with no peripheral blood or lymph node involvement. o Pathogenesis: several genes are involved in the pathogenesis of PCM, these include cyclin D1, cyclin D3, TP53, and IgH (keep in mind that cyclin D1 is not specific for mantle cell lymphoma as it can be seen in plasma cell myeloma). o Diagnosis: the diagnosis of PCM depends on the demonstration of monoclonal plasma cells in the bone marrow, monoclonal proteins in the serum and end organ damage (defined as anemia (done by CBC), renal dysfunction (done by serum tests for creatinine), hypercalcemia (serum tests for calcium) or lytic bone lesions(by x-rays); remember them with the abbreviation CRAB: Calcemia, Renal dysfunction, Anemia, and Bone lesions). o Keep in mind that, unlike all other B-cell neoplasms which have monoclonal kappa or lambda on their surface, plasma cell myeloma cells also secrete these monoclonal antibodies in the serum, therefore monoclonality can be proved by simple serum tests without the need to actually examine the cells, this serum test is called protein electrophoresis. o Clonal antibodies can be found in the serum or in urine § In urine, only light chains can pass (only kappa or lambda can pass but not heavy chains). In urine these monoclonal light chains are called Bence Jones proteins, named after the scientist who discovered them. Protein electrophoresis: The patient’s serum is subjected to an electrical current, the movement of the proteins in the serum to different locations depends on their size and electric charge. In PCM the number of clonal antibodies will be higher than normal and will show a narrow peak in contrast to normal people who show a short broad peak because they have a small number of polyclonal antibodies. The presence of this narrow high peak is called “M protein” (M stands for monoclonal). o Immunophenotype: in spite of being a B-cell neoplasm, B cell markers (CD19, CD20, CD22, CD79 and pax5) are not expressed!! o Instead, CD138 and CD38 are expressed, these markers are specific for PCM o Either kappa or lambda as this tumor is monoclonal o Morphology: the plasma cells are large with abundant basophilic cytoplasm, perinuclear clear areas, round nuclei with clumped chromatin that look like bike wheels. Sometime vesicles filled with monoclonal antibodies will be noted in the cytoplasm or the nucleus, these are called Russel bodies and Dutcher bodies respectively. (A good way to remember them is that “Dutcher” starts with a “D” like the DNA and hence it’s nuclear, and “Russel” starts with an “R” like RNA and so it’s in the cytoplasm!!!) o Note the neoplastic plasma cells with their abundant blue cytoplasm and frequent Russel bodies. o Prognosis: indolent disease with variable survival, this disease is not curable. Hodgkin lymphoma (HL) o Definition: A common B-cell neoplasm characterized by the presence of large atypical cells called Reed-Sternberg cells in a background of benign inflammatory cells. o Classification; HL is divided into two groups: o Classic HL which is further divided into four subclasses: § Nodular sclerosis HL o o o o § Mixed cellularity HL § Lymphocyte rich HL § Lymphocyte depleted HL Nodular lymphocyte predominant HL (NPL-HL, don’t confuse it with lymphocyte rich classic HL!) Clinical presentation: typically affects young adults, usually with limited disease to the cervical and mediastinal areas. Systemic symptoms such as fever, weight loss and night sweats (collectively known as the B symptoms) are common in HL. Rarely involves tonsils, Waldeyer ring or extranodal sites. Pathogenesis: HL is a B-cell neoplasm with dysregulated B-cell machinery. The key element is the upregulation of the transcription factor NF-KB by several mechanisms including infection by EBV. Diagnosis: the key morphologic element in diagnosis is the presence of large, atypical cells with abundant clear to eosinophilic cytoplasm, showing atypical and sometimes binucleated nucli with prominent large nucleoli, these cells are called Reed-Sternberg cells named after the people who described them. Unlike other types of lymphoma, the vast majority of the cells in the tissue are composed of reactive benign inflammatory cells including eosinophils, neutrophils, lymphocytes, plasma cells and macrophages. Thick bands of fibrosis are seen in the nodular sclerosis subtype of classic HL. § Immunophenotype: there is a difference between the immunophenotype of classic HL and NPL-HL • Classic HL: the neoplastic cells are positive for CD30 and CD15 in addition to Pax5 (the only positive B-cell marker in HL). In spite of being a B-cell neoplasm, all other B-cell markers are negative (CD20, CD22, CD79, and CD19). CD34 and CD 45 are negative. • NPL-HL: is positive for B-cell markers and negative for CD30, CD34 and CD15. CD45 is positive. Morphology) RS)cells)) o o o In this image note the thick sclerotic bands surrounding cellular islands containing RS cells and abundant reactive inflammatory cells. Note the presence of various benign cellular elements including eosinophils and plasma cells. Also note the large RS cell. o Prognosis: generally good prognosis due to low stage at presentation, cure rate for low stage disease is ~80—90% and even for more advanced disease the cure rate approaches 50%. Marginal zone lymphoma of the mucosa associated lymphoid tissue (MALToma). o Definition: an extranodal B-cell neoplasm of memory B-lymphocytes arising in tissues in the setting of chronic inflammation. o Examples include: thyroid tissue in the setting of Hashimoto thyroiditis. o Salivary gland in the setting of Sjögren syndrome. o Stomach in the setting of chronic gastritis caused by H.pylori. o Pathogenesis: chronic inflammation recruits a large number of reactive lymphocytes. With time, genetic mutations occur in a subset of cells giving them a survival advantage, thus proliferating and taking over the tissue. o Evidence of the role of inflammation comes from the fact that some tumors actually regress with treating the underlying inflammation, for example, eradicating the H. pylori infection results in resolution of the tumor without the need for chemotherapy. o Clinical presentation: masses in the involved organs. Some nonspecific gastric symptoms can occur such as pain, reflux and nausea. o Morphology: the epithelium of the involved organ is attacked and damaged by small to medium-sized lymphocytes showing round nuclei, clumped chromatin and indistinct nucleoli (lymphoepithelial lesion). o Immunophenotype: B-cell markers are positive in addition to monoclonality by kappa or lambda. o Negative for CD5 and CD10. o Note in the image the presence of epithelial damage by the neoplastic lymphocytes. Hairy cell leukemia (HCL) o Definition: A rare distinctive B-cell neoplasm that typically involves the spleen, liver and peripheral blood with no lymph node involvement (hence the name: leukemia) o Epidemiology: rare tumor representing 2% of all leukemias, median age of patients is 55 and males are much more likely to be affected than females. o Pathogenesis: the vast majority of cases have a mutation in the BRAF gene, which is part of the MAPK pathway that promotes cell growth. (Remember that BRAF mutations are present in many other tumors including melanoma, some colon cancers, and Langerhans cell tumors). o Clinical presentation: splenomegaly with pancytopenia is the typical presentation, hepatomegaly can be seen but lymphadenopathy is rare. Pancytopenia results from bone marrow infiltration and can cause infections, anemia and bleeding. o Diagnosis: in the peripheral blood the cells are intermediate in size with cytoplasmic hairy extensions. In the spleen, the splenic red pulp is filled with neoplastic cells. (Please remember that most other lymphomas such as DLBCL, FL and marginal zone lymphoma affect the white pulp when they involve the spleen, HCL, however, is a disease of the red pulp). o Immunophenotype: B-cell markers with monoclonal kappa or lambda expression § Additionally, HCL expresses some distinctive markers such as CD11c, CD25, CD103 and CD123. o Note the cytoplasmic, circumferential hairy extensions around the lymphocytes. o Prognosis: Indolent course with excellent prognosis, very sensitive tumor to chemotherapy. Mycosis fungoides (MF) o Definition: a mature T-cell neoplasm of CD4+ helper cells typically affecting the skin (the name is a misnomer as it has no relation to fungal infections!) o Epidemiology: most patients are elderly but the tumor can affect any age, males are affected more commonly than females. o Clinical presentation: the disease presents in three stages: first the patch stage, then the plaque stage and finally the tumor stage. The progression is slow and may take years to decades to reach the tumor stage. Erythroderma refers to the presence of red patches all over the body and is considered a very advanced stage of the disease. o Diagnosis: the disease is limited to the skin in the vast majority of cases; there is a dermal infiltration of small to medium sized nuclei with irregular “cerebroid-like” borders that infiltrate the epidermis. These cells are positive for CD3 and CD4 and negative for CD8. o o Prognosis: indolent disease with prolonged survival in the early stages, however, if progression to tumor stage or to Sezary syndrome (circulating neoplastic cells in the peripheral blood) then median survival is 1-3 years.