PTH LEC - LE 2, 6A - Diseases of the WBC, Lymph Nodes & Spleen I (V1) PDF

PATHOLOGY | TRANS 6A LE Diseases of the WBC, Lymph Nodes & Spleen I ARACELI P. JACOBA, MD, FPSP | Lecture Date (10/04/2024...

PATHOLOGY | TRANS 6A LE Diseases of the WBC, Lymph Nodes & Spleen I ARACELI P. JACOBA, MD, FPSP | Lecture Date (10/04/2024) | Version #1 02 OUTLINE → Increased destruction I. Benign Conditions IV. Peripheral lesions ▪ Ig-mediated injury A. Leukopenia A. Peripheral B Cell − Associated with a well-defined immunologic B. Benign Proliferations Neoplasms disorder (e.g SLE) II. Lymphoma B. Peripheral T Cell − May also be drug induced A. Neoplastic Neoplasms ▪ Increased peripheral utilization Proliferations C. Hodgkin’s Lymphoma − Due to overwhelming bacterial, fungal infection III. Precursor lesions V. Summary A. Precursor T Lymphoma VI. Review Questions − WBC are used up or disintegrate while performing B. Precursor B Lymphoma VII.References its function to rid the body of bacteria and foreign bodies. Must Lecturer Book Previous Youtube − Consumption of leukocytes following ❗️ Know 💬 📖 📋 Trans 🔺 Video overwhelming infection (bacterial, fungal pr Rickettsial infections) SUMMARY OF ABBREVIATIONS ▪ Splenic sequestration HL Hodgkin’s Lymphoma − Spleen also sequesters WBCs as much as it RS Reed Sternberg Cells sequesters RBCs and platelets SR Survival Rate − Similar to sequestration of platelets when the BM Bone marrow enlarged spleen increases volume of cells bring LN Lymph nodes sequestered to 80-90% Proliferative states LEARNING OBJECTIVES → Proliferation of WBC should be differentiated if it is ✔ To understand the pathogenesis (gene defects), benign or malignant laboratory abnormalities (including immuno- → Since there are 2 sources of WBC, there will be different histochemistry), morphology & symptomatology of manifestations. Diseases of WBC with emphasis on Lymphoma, A. BENIGN PROLIFERATIONS Leukemia, and Multiple Myeloma Proliferative States I. BENIGN CONDITIONS → More common as compared to leukopenic A. LEUKOPENIA → Proliferation of WBC should be differentiated if it is Decrease in circulating WBCs in blood benign or malignant Causes of Leukopenia are similar to what we see in → Unlike RBCs, there are 2 sources of WBC: anemia or thrombocytopenia (since WBCs also come from ▪ Bone marrow (BM) - cells of the bone the bone marrow) ▪ Lymph nodes (LN) An abnormally low white cell count usually results from → Since there are 2 sources of WBC, there will be different reduced numbers of neutrophils (neutropenia, manifestations. granulocytopenia) A. Reactive or benign proliferation: Causes: a. In BM, it spills into peripheral circulation and is → Ineffective granulopoiesis called leukocytosis. ▪ Present in aplastic anemia or B12 deficiency b. In LN, it is a response to sites draining an ▪ Mechanisms: infection and called lymphadenitis. − Suppression of stem cells B. Neoplastic or malignant proliferation of WBC: o Aplastic anemia a. BM is seen in leukemia. o Drugs - the most common cause of b. LN is seen in lymphoma. agranulocytosis is drugs - alkylating agent and Table 1. Major sources of WBC antimetabolites in CA treatment Bone Marrow Lymph Node = Have the propensity to decrease the WBC by Reactive/Benign Leukocytosis Lymphadenitis several mechanisms Neoplastic/Malignant Leukemia Lymphoma = Antimetabolite activity of chemotherapeutic drugs (alkylating and antimetabolite agents) REACTIVE PROLIFERATION OF WBC IN SMEARS suppresses the bone marrow as a whole. Leukocytosis = Antipsychotic drugs (like chlorpromazine and → The proliferation of a particular type of WBC can help phenothiazines) have toxic effects on you arrive at the possible etiology of the disease. granulocytic precursors ▪ Neutrophilia = Most drugs are idiosyncratic − bacterial infection, tissue necrosis = come have antibody mediated destruction of ▪ Lymphocytosis neutrophils similar to autoimmune hemolytic − chronic infection, viral, immunologic anemia (AIHA) in RBCs ▪ Eosinophilia − Ineffective maturation − asthma, allergy, parasitic o B12 deficiency ▪ Monocytosis − Congenital − chronic infection, collagen disorders (SLE) o Kostmann Syndrome: a congenital cause of severe chronic neutropenia LE 2 TG 16&17 | Lim P, Lim S, Lin, Loresza, Lubag, TE | Lim M, Luna AVPAA | R. Manalili PAGE 1 of 18 TRANS 6A Lucena, Lugo, Mabansag, Madayag VPAA | A. Escolano PATHOLOGY | LE 2 Diseases of the WBC, Lymph Nodes & Spleen I | Araceli P. Jacoba, MD, FPSP Leukemoid reaction as darker and larger blue granules that represent → Term given to overwhelming bacterial infection or sepsis increased lysosomal activity in preparation for that the neutrophilic response reaches the level of phagocytosis. leukemia Presence of immature forms like stabs, → “-oid” means similar to, so a leukemoid reaction is metamyelocytes or myelocytes similar to leukemia in terms of WBC counts → The stab is the cell prior to the neutrophil → Marked elevation of the WBC due to severe → Stabs appear as kidney shaped or C- cells without the inflammation filamentous connection of the lobes in a mature → There will be immature forms and shift to the left neutrophils → The main difference however is the absence of blast → This is the earliest cell in peripheral blood. Normal value cells in leukemoid reaction for stabs in a normal CBC is only 3%. ▪ presence of blast cells will indicate malignancy → Values may be increased during an infection. Peripheral Blood Smear (PBS) changes Neutrophilia → Changes in the neutrophils → The normal value for neutrophils in a differential count is ▪ Toxic granules 40-70% of total WBC count. − Indicates increased activity of neutrophils in the → In an inflammatory response like bacterial infection, the production of enzymes and protein needed for number of neutrophils exceeds the upper limit of 70% phagocytosis and replaces other types of WBC in blood. − These proteins assume increased lysosomal → In the case of neutrophilia, the levels of lymphocytes activity leading to granulation in the cytoplasm become exceedingly low. ▪ Dohle bodies − Light blue smudged cytoplasmic patches representing dilated endoplasmic reticulum again reflective of the increased activity of WBC during an infection ▪ Shift to the left − Indicates increased number of young forms of myeloid cells particularly stabs and metamyelocytes in peripheral blood − In infection, the bone marrow tend to increase the volume of production and release even young forms to compensate for the losses in peripheral circulation − Remember that during bacterial killing to fight Figure 2. Reactive changes in the Peripheral smear seen in infection, the WBC dies with the engulfed foreign Neutrophils. (continuation) material. − Thus in infection, inflammatory mediators increase Dohle bodies the volume of WBC produced and release even → a dilated endoplasmic reticulum, sky blue cytoplasmic young stages to peripheral circulation. puddles − No matter how intense the WBC produced by the → Representing increased lysosomal activity in BM, blasts should never appear in peripheral neutrophils. blood in an infection. Atypical lymphocytes − The presence of blasts indicates Malignancy. → reactive changes in lymphocytes to viral or fungal → Changes in the lymphocytes infection ▪ Enlargement of the cell with abundant cytoplasm ▪ enlargement of the nuclei and the cell as a whole called atypical lymphocytes ▪ no increase in N:C ratio ▪ Cytoplasm remains abundant with soft cytoplasmic borders. Note that the cytoplasm is easily indented by an adjacent red cell. Figure 1. Reactive changes in the Peripheral smear seen in Neutrophils. Toxic granules → Note prominence of bluish granules in the cytoplasm Figure 3. Reactive changes seen in the Peripheral blood. → Neutrophils have fine powdery granules not very visible Figure 3 indicates a bacterial infection. Notice the normally following changes: → These powdery fine granules become bigger and seen → Shift to the left with increased number of stabs and PATHOLOGY Diseases of the WBC, Lymph Nodes & Spleen I Araceli P. Jacoba, MD, FPSP PAGE 2 of 18 PATHOLOGY | LE 2 Diseases of the WBC, Lymph Nodes & Spleen I | Araceli P. Jacoba, MD, FPSP some myelocytes. No blasts 4. The stimulation of CD4 helper cells causes enlargement → Neutrophilia. The predominant cell type is neutrophils of small virgin resting collars of B cells at the periphery of with only 2 lymphocytes in the smear. Rough estimate the lymphoid follicles. of neutrophils here is 85% (normal neutrophil differential 5. These activated B cells enter the germinal center in count is 40-70%). preparation for bacterial killing REACTIVE PROLIFERATION OF WBC IN LYMPH NODE 6. B cells that survive the struggle in the germinal center differentiate to plasma cells, migrate to the medullary Acute Lymphadenitis cores → Reactive change 2 to microbiologic agents and their 7. Leave the node carrying with them an imprint of the toxic products intruder to continuously monitor the body of this intruder. → Foreign bodies or cell debris → Reactive changes in the nodes draining bacterial infection and necrotic debris Chronic Lymphadenitis → Follicular hyperplasia ▪ B cell stimulation (B cells are located within follicles). Mostly due to viruses ▪ i.e. RA, Toxoplasmosis, HIV (early stage) → Parafollicular hyperplasia / Paracortical hyperplasia ▪ T cell stimulation (T cells are located in the parafollicular areas). Mostly related to vaccination/ drugs ▪ i.e. drugs, IM, vaccines → Sinus histiocytosis ▪ Seen in nodes draining cancer sites (histiocytes are abundant in the medullary sinuses) ▪ Reticular hyperplasia seen in cancer Figure 5. Normal lymph node, microscopic. Note the following: MZ or mantle zone - contains small inactive resting dark blue unstimulated sleeping B cells located in the collar of a lymphoid follicle GC or germinal center - contains activated B cells that are larger, irregular nuclei that are cleaved and appear pale. When there is increased activity of the node when fighting infection, the following changes are observed → The germinal center enlarges with enlargement of nuclei that appear pale. → Thinning of the inactive collar of blue small unstimulated cells at the mantle zone which is the periphery of the lymphoid follicle. Figure 4. Normal lymph node, microscopic. Note the following: Subcapsular sinuses (orange star) Medullary sinuses (yellow star) B - follicles that contains B lymphocytes Bs (inactive, sleeping B cells) Ba (active war-ready B cells) T - parafollicular area that contains T lymphocytes and macrophages T killer - kills virus, Ca cells T-helper (CD4) - send signal to B cells thru Th2 cells and sends signals to macrophage for phagocytosis Normal lymph node reaction to foreign body: 1. As antigens/foreign body enter the node, they flow along afferent lymphatic channels 2. Dumped to the subcapsular sinuses 3. Pass through the parafollicular trabeculae and are processed or killed by T lymphocytes, macrophages or Figure 6. Follicular hyperplasia, microscopic. Note the APCs. Macrophages or CD8 killer T cells kill it if able. following changes: Those that cannot be killed by the macrophage or CD8 Thinning of the collar of resting unstimulated B cells killer are processed by APC and CD4 helper T cells. The Germinal centers are polarized into 2 – centroblast (dark CD4 helper cells transmit signals to B cells in the follicles. PATHOLOGY Diseases of the WBC, Lymph Nodes & Spleen I Araceli P. Jacoba, MD, FPSP PAGE 3 of 18 PATHOLOGY | LE 2 Diseases of the WBC, Lymph Nodes & Spleen I | Araceli P. Jacoba, MD, FPSP zone) and centrocyte (light zone). The unstimulated blue II. LYMPHOMA lymphocytes in the mantle zone undergo the following A. NEOPLASTIC PROLIFERATIONS changes. First the centroblast which are enlarging cells According to cell origin that still have darkly stained nuclei. The centroblast later → Lymphoid Neoplasms develops fully to a centrocyte, a complete warrior with ▪ Lymphoma more abundant light colored cytoplasm carrying with it all ▪ Leukemia the weapons for war. Interspersed between the → Myeloid Neoplasms centrocytes and centroblasts are the APCs and the larger → Plasma cell Dyscrasias macrophage. → Histiocytosis TANGIBLE BODIES are nuclear debris within the macrophage that are considered the spoils of war. Figure 7. Lymphoid follicle with an active germinal center. Note the following: Figure 9. Normal Hematopoiesis Green star - mantle zone of inactive B lymphocytes which is thin LYMPHOID NEOPLASMS Orange star- centroblasts stimulated from the inactive Lymphoma - arise in nodal tissue lymphocytes. The centroblasts are located nearer the → B or T cell inactive B mantle zone → Precursor or Peripheral Yellow star – centrocytes develop from centroblasts and Lymphocytic Leukemia - arise in BM located farther from the inactive B mantle zone → Chronic Lymphocytic Leukemia (CLL) Presence of tangible bodies in the macrophages → Acute Lymphocytic Leukemia (ALL) Polymorphic cells in the germinal centers. This means WHO CLASSIFICATION OF LYMPHOID TUMORS that the centers contain a variety of cells that include your Precursor B cell (pre B cell) centroblasts, centrocytes and macrophages. → B lymphoblastic Leukemia (ALL) / lymphoma Precursor T cell (pre T cell) → T lymphoblastic Lymphoma / Leukemia Peripheral B Cell → CLL, SLL, Burkitt's Lymphoma, Follicular lymphoma, Hairy cell leukemia Peripheral T Cell or Natural Killer cell → Adult T cell lymphoma, NK-T cell lymphoma, Mycosis Fungoides / Sezary syndrome Hodgkin's Lymphoma Figure 8. Follicular hyperplasia. Note the following changes: Increased number of follicles not limited to the cortex and present also in the medulla Enlarged active germinal centers Thin inactive blue collar Clear contrast and well defined margin between the active germinal center (pale pink color) and inactive B mantle zone. (dark blue color). Malignant follicles will not have clear contrast between the active zone and inactive zone. Figure 10. B and T Cell Neoplasms PATHOLOGY Diseases of the WBC, Lymph Nodes & Spleen I Araceli P. Jacoba, MD, FPSP PAGE 4 of 18 PATHOLOGY | LE 2 Diseases of the WBC, Lymph Nodes & Spleen I | Araceli P. Jacoba, MD, FPSP CELL ANTIGENS IN WBC Table 2. Cell Antigens in WBC CELL ANTIGEN PRESENT LCA CD45 T Cell CD1 CD5 CD4 / CD8 CD3 B Cell CD10 - germinal center B CD 19, CD20 - pre B, mature B CD23 - mature B IgM - plasma cells Figure 12. Gross Appearance of a Lymphomatous Node Monocyte/ CD11 Macrophage CD13 Gross appearance of LN affected with lymphoma: CD14 → Node is enlarged CD15 → Cut section shows fish flesh surfaces that bulges CD33 above the cut surface CD64 → Margins are irregular that can invade the capsule NK Cell CD16 CD56 Stem Cell CD34 Hodgkin's CD15 CD30 GENERAL CHARACTERISTICS OF LYMPHOID TUMORS Monoclonal Population Mostly B cells (85% - 95%) Each type has its own clinical presentation Associated with immune abnormalities Figure 13. Paratracheal LN identified by black carbon Recapitulate behavior of normal counterparts pigments → Homing of neoplastic cells Gross findings in lymphoma: → Vascular recirculation → Coalescent nodes that are enlarges and varying sizes → The cut section has a “fish flesh” appearance. → The coalescence is due to the tumor extending beyond the capsule to invade the adjacent node. The black areas are carbon pigments indicating that these are perihilar nodes in the lungs. Figure 11. (L) Follicular hyperplasia; (R) Follicular lymphoma Figure 14. Gross appearance of lymph nodes involved by SYMPTOMS non-Hodgkin lymphoma of the diffuse large cell type. Lymphadenopathy Enlarged coalescent paracolic nodes in the GIT with fleshy → multiple appearance of cut section → painless Nodes are large and show a homogenous tan cut surface. Nonspecific: III. PRECURSOR LESIONS → fever, malaise WHO Classification of Lymphoid Tumors → weight loss → Precursor B cell (pre B cell) Extranodal involvement ▪ B lymphoblastic Leukemia (ALL) / lymphoma → primary → Precursor T cell (pre T cell → extension ▪ T lymphoblastic Lymphoma / Leukemia → Peripheral B Cell → Peripheral T Cell or Natural Killer cell → Hodgkin's Lymphoma PATHOLOGY Diseases of the WBC, Lymph Nodes & Spleen I Araceli P. Jacoba, MD, FPSP PAGE 5 of 18 PATHOLOGY | LE 2 Diseases of the WBC, Lymph Nodes & Spleen I | Araceli P. Jacoba, MD, FPSP These are immature cells that originate from the source of ▪ Chronic Lymphocytic Leukemia: when SLL spills the tumor cells — either the bone marrow (Precursor B) or into the blood with lymphocyte count of >4,000 in Thymus (Precursor T). peripheral blood. The marker for precursor tumors is Terminal Common complications of SLL that may ensue: deoxynucleotidyl transferase or TdT. This is seen in all → Hypogammaglobulinemia with increased tendency to precursor lesions whether B or T. infection. → All precursor lesions will be positive for this marker. → Hemolytic anemia or Thrombocytopenia A. PRECURSOR T LYMPHOMA ▪ Due to production of autoimmune antibodies (Abs) by non-neoplastic B cells. There is only one type: Acute lymphoblastic lymphoma or ▪ Recall: Warm AHA are caused by tumors by leukemia (pre T ≈ T-ALL) lymphomas. This tumor originates from the immature cells in the → Transformation to Large B Cell (10%) 📋 thymus. It is a lymphoblastic lymphoma originating from very immature T cells of the thymus that have not ▪ A more aggressive form of lymphoma called the Richter Syndrome ▪ Ominous event and when it happens, the survival is differentiated to either CD4 or CD8, calling these blast shortened to 1 year after the transformation. cells as Double Negative Pre T Cells. Chromosomal abnormalities are rare unlike other The lesion or tumor is usually a rapidly enlarging lymphoid tumors: symptomatic mediastinal mass corresponding to the → More consistent are: location of the thymus in 70% of the cases. ▪ Trisomy 12 This is usually seen in adolescent males. ▪ Deletions of chromosomes 13q, 11q, and 17p. These are aggressive tumors that are rapidly fatal if Immunophenotype: untreated with 60-80% remission upon treatment → B Cells: CDE 19, 20, and 23. Symptoms are due to lymphadenopathy and → Presence of a T Cell marker CD5 splenomegaly. ▪ Present only in 2 B cell tumors: SLL and Mantle Cell B. PRECURSOR B LYMPHOMA Lymphoma Also called as “Acute Lymphocytic Leukemia” (Pre B ≈ ▪ This can help differentiate and diagnose SLL from B-ALL) other B Cell Lymphomas since most peripheral 📋 Originates from the bone marrow that spills into the blood It is a lymphoblastic leukemia that originates from the most immature blast cells in the bone marrow called tumors produce only B Cell Markers. Since this is an indolent tumor with a long course, it is necessary to identify markers (factors) that will indicate a Common Lymphocytic Precursor (CLP) or Pre B more aggressive course. Lymphoblast (BLB). → These are markers for poor prognosis factors: → It presents as leukemia, specifically Acute Lymphocytic ▪ High tumor load (levels above 200,000) Leukemia Very common in children (4,000 cells → Symptoms wax and wane that are unaffected by in the peripheral blood. treatment. → Absolute lymphocyte count is derived from the WBC → Can transform to an aggressive form of Diffuse Large B count x % of lymphocytes in the differential count. Cell Lymphoma particularly if they carry a bad gene, ▪ E.g. WBC count: 20,000, Differential Count: 50% c-MYC gene. − Absolute lymphocyte count = WBC Count x % Treatment Protocol: Lymphocytes in Differential Count = 10,000 → “Watch and wait” attitude for treatment because the o Since >4,000, it is considered as CLL rather disease is unaffected by treatment. than SLL or lymphoma. 📋 → Treatment is only given when symptomatic. The median survival is less than 1 year after 📋 → WBC count: Low ( ↓ ) in SLL, High ( ↑ ) in CLL CLL is the common leukemia in adults in the Western world. 📋 transformation. Immunophenotype: B Cells (CD10, C19, C20) plus Bcl 2 protein. Figure 16. Peripheral Blood Smear of CLL Refer to Figure 16 for the appearance of CLL in the peripheral blood smear. Note the following changes: Figure 17. Follicular Lymphoma, LPO → Increased WBC Count with predominance of small Figure 17 shows Multiple nodular aggregates of lymphocytes. lymphoblasts that replace normal nodal architecture ▪ Normal WBC Count will only show 3-4 WBCs per oil (present throughout the node). immersion field with a mixture of both neutrophils and Cortex and medulla all replaced by tumoral follicles lymphocytes. This is in contrast to Figure 16, which Note invasion of the capsule and invasion of adjacent shows a slide that is purely lymphocytic giving a clue adipose tissue by the tumor (black arrow). to the diagnosis of lymphocytic leukemia. Normal architecture of the node with follicles limited in the → Monomorphic appearance of only lymphocytes in cortex is not seen in cases of lymphoma. smear. No other cells present. → Appearance of “smudged cells” (refer to the black arrow) will give a clue to the diagnosis. ▪ These are pale cells that appear flattened, larger than the adjacent lymphocyte, no definite nuclei and irregular smudged margins. PATHOLOGY Diseases of the WBC, Lymph Nodes & Spleen I Araceli P. Jacoba, MD, FPSP PAGE 7 of 18 PATHOLOGY | LE 2 Diseases of the WBC, Lymph Nodes & Spleen I | Araceli P. Jacoba, MD, FPSP Figure 18. Comparison of Follicular Lymphoma (L) and Follicular Hyperplasia (R) Figure 19. Histology: Mixture of Centrocytes and 💬 Follicular lymphoma Uniform appearance throughout, making it difficult to Centroblasts Left picture shows the gross morphology of Spleen 💬 💬 differentiate Proliferation of just one single type of cell Invasive as it infiltrated the adipose affected by lymphoma. → Prominent multiple small nodules that represent expanded follicles. 💬 Follicular Hyperplasia 💬 Has lymph nodes similar to lymphoma Benign, well defined area between the immature B cells → This pattern of infiltration is seen not only in Follicular lymphomas but other forms of Lymphomas as well Right picture shows the histology of Follicular lymphoma 💬 and the active germinal area Germinal center of follicle is a “war zone”, where our lymphoid cells fight off foreign bodies, viruses, tumor → The cells recapitulate the centroblasts and centrocytes in a germinal center and are mixed with each other compared to the polarized arrangement in a 💬 cells, different exogenous materials that enter our body Lighter staining cells (almost white) found in the normal germinal center where the centroblasts are near the mantle zone and the centrocytes are in the 💬 germinal centers are immunoblasts ”Sleeping soldiers” are on the periphery, blue inactive center of the germinal center. → Centrocytes are small lymphoid cells with condensed 📋 💬 cells Well encapsulated Table 3. Comparison of Follicular Lymphoma and chromatin and irregular cleaved nuclear outline → Centroblasts are large cells w/ several nucleoli (black arrows) Follicular Hyperplasia → The rest of the cells are Centrocytes. Follicular Hyperplasia Follicular Lymphoma Benign Malignant Follicles are polymorphic Follicles show monomorphic cells Clear well defined margin No clear margin between between the germinal center germinal center and inactive and inactive mantle zone mantle zone Cells in the germinal center Pinpoint spaces occupied by will show pinpoint pale areas the macrophages are lost due to the macrophages and the proliferation is limited by the capsule No invasion of capsule Invasion of capsule and adjacent fat Figure 20. Bcl-2 Stain comparing the staining characteristics of a reactive follicle and a follicular lymphoma Figure 20, left picture: In a benign follicle, Bcl-2 stains only the inactive lymphocytes of the mantle zone and none in the germinal centers. Figure 20, right picture: In a malignant follicle, all stains are being stained whether it is in the central zone or peripheral zone. The function of the Bcl-2 is to antagonize apoptosis and promote survival of the follicular lymphoma cells. PATHOLOGY Diseases of the WBC, Lymph Nodes & Spleen I Araceli P. Jacoba, MD, FPSP PAGE 8 of 18 PATHOLOGY | LE 2 Diseases of the WBC, Lymph Nodes & Spleen I | Araceli P. Jacoba, MD, FPSP → Apoptosis and cell death is a normal occurrence in the Figure 21. Spleen affected by Diffuse Large B Cell 📋 germinal center. Germinal center cells cause bacterial killing and it is the place where lymphocytes die after Lymphoma Left picture shows a spleen involved in Diffuse Large B Cell Lymphoma (DLBCL) 📋 clearing enemies. However, in a Bcl-2 abnormality, the lymphocytes undergo immortality with no apoptosis or cell death, → More often, there is an isolated large expansile destructive mass noted in the organ that is involved. ▪ Rapidly enlarging mass commonly affecting a node resulting in tumor. or an extranodal site. DIFFUSE LARGE B-CELL LYMPHOMA (DLBCL) → Notice the fleshy or fish flesh appearance of lymphomas on the cut section. Epidemiology: seen in elderly patients (median patient Right picture shows histology of DLBCL that consists of age is 60 years old) with a small percent seen in pediatric very large cells, usually 5x bigger than the normal patients (5%) lymphocytes with moderately abundant cytoplasm and Course and behavior: aggressive tumor that is rapidly nuclei that contain prominent nucleoli. fatal if left untreated → Mitosis is usually increased in this tumor. → Upon treatment or chemotherapy, some of the cases → This type of tumor may be difficult to differentiate from a achieve complete remission and cure in half of the metastatic carcinoma, in which case the LCA and CD patients (60-80%). clusters for B Cells will be needed to differentiate the → In contrast with Follicular Lymphoma which is an two. indolent, slow growing tumor but incurable and no → These cells resemble immunoblasts, thus, another response to treatment. name for this tumor is Immunoblastic Lymphoma. Symptoms: → Rapidly enlarging symptomatic mass at a single nodal BURKITT’S LYMPHOMA or extranodal site. ▪ Nodal sites: can be the tonsils & adenoids, with 📋abundant lymphoid tissues. Waldeyer ring, the oropharyngeal lymphoid tissue, is commonly involved. The median survival is less than 2 years after transformation. ▪ Extranodal site: GIT, skin, bone, brain, with secondary involvement of spleen & liver. − It affects more extranodal tissues rather than the lymph nodes. ▪ Spleen and the liver can be the origin of the tumor or can be involved from secondary spread elsewhere. → Rarely involves the bone marrow such that a leukemic picture is not seen in DLBCL 📋 Cytogenetics: Bcl-6 (30%) and Bcl-2 (10%) → This tumor has good response to treatment but Figure 22. Types of Burkitt’s Lymphoma presence of the c-MYC gene indicates a poor Epidemiology: Children (30%) and young adult prognosis or high treatment failure. Symptomatology: Tumors are mostly extranodal Immunophenotype and abnormal genetics: → Endemic types (refer to Figure 22) affect mandible of → Immunophenotype for B cells (CD19, C20, CD10) and face & pelvis (affecting organs like ovary, kidney, & Bcl 6. adrenal) ▪ However, Bcl 6 is seen only in a third of cases and ▪ The patient has a mass in the mandible - main not as consistent as Bcl 2 in Follicular Lymphomas. characteristic of endemic type Burkitt’s Lymphoma ▪ BcL-6, controls differentiation and inhibits p-53. ▪ Endemic type of BL are latently infected with the EBV virus, which is also present in about 25% of HIV-associated tumors and 15-20% of sporadic cases. → Non-endemic or Sporadic types (refer to Figure 22) affect the abdomen (ileum, cecum, and peritoneum). There is also a subset of aggressive lymphomas occurring in individuals infected with HIV. Course and prognosis: → very aggressive, rapidly progressive with good response 💬to chemotherapy One of the fastest growing tumors in humans → Children and young adults can be cured but outcome is poorer in older patients Histology: → Monotonous sea of intermediate sized lymphoid cells → Interspersed with phagocytes with abundant clear cytoplasm producing a “starry sky” pattern. → Tumor exhibits high mitotic index with nuclear apoptotic PATHOLOGY Diseases of the WBC, Lymph Nodes & Spleen I Araceli P. Jacoba, MD, FPSP PAGE 9 of 18 PATHOLOGY | LE 2 Diseases of the WBC, Lymph Nodes & Spleen I | Araceli P. Jacoba, MD, FPSP debris within benign macrophages. Apoptotic debris (yellow arrow) Immunophenotype: → The apoptotic debris can be seen engulfed by the → B cell markers (CD10, CD19, CD20) plus IgM and BCL6 macrophages or scattered between the tumor cells Pathogenesis: Macrophages with abundant white cytoplasm, representing → Associated genetic abnormality: t(8;14) of c-MYC gene the stars in a background of diffuse spread of dark blue 📋 → Associated with EBV (Epstein-Barr Virus) Endemic Burkitt’s Lymphoma → Latently infected with the EBV virus, which is also lymphocytes MANTLE CELL LYMPHOMA Epidemiology: 50-60 y/o (5th to 6th decade of life), with present in about 25% of HIV-associated tumors and male predominance; IR: 3% US, 7-9% UK 15-20% of sporadic cases. Symptomatology: All forms of Burkitt’s Lymphoma → Produces generalized painless lymphadenopathy with → Are highly associated with a translocation of the MYC extranodal spread (i.e., bone marrow [40-60%], spleen gene on chromosome 8 that leads to increased MYC [50%], liver, GIT) protein levels ▪ Affects the BM in more than half of cases causing it → Warburg Effect to spill in the blood and spread to other organs ▪ Increase expression of genes that are required for − Follicular Lymphoma or Small Lymphocytic aerobic glycolysis caused by MYC, a master Lymphoma: only affects the lymph nodes transcriptional regulator − Diffuse Large B-cell lymphoma (DLBCL): only affects the extranodal organs − Mantle Cell Lymphoma (AKA Disseminated Lymphoma): Lymph nodes, extranodal organs and peripheral circulation are affected, making it an aggressive tumor that spreads widely ▪ Because of the extensiveness of the lesions with generalized lymphadenopathy and spread to other organs, it is called as disseminated lymphoma → Lymphomatoid polyposis ▪ Multiple polypoid lesions in the GIT Immunophenotype: → (+) CD19, CD20, CD5 → (-) CD23 → B cells with CD5 which is a T cell marker ▪ It is one of the B cell tumors that secrete a T cell marker → Note: This tumor is CD23 negative which distinguishes it from the slow growing tumor of Small Lymphocytic Lymphoma (SLL) which is CD23 positive (but also CD5 Figure 23. Starry sky pattern of Burkitt’s Lymphoma positive) The tumor is made up of diffuse neoplastic dark blue Genetic abnormality: t(11:14); Overexpression of cyclin lymphocytes representing the “sky” interspersed by larger D1 → This mutation promotes the G1 to S phase of the cell 💬 benign macrophages representing the “stars” Histiocytes which are considered two stars in a blue cycle. Abnormality is present in almost all cases. Course and Prognosis: 💬 background (lymphocytic proliferation) High turnover rate therefore there are a lot of nuclear debris, some histiocytes will contain nuclear debris → Aggressive and not curable (3-5 years survival rate) ▪ Worst type of lymphoma → Prognosis is very poor Figure 24. Burkitt’s Lymphoma Figure 25. histology of Mantle Cell Lymphoma High mitotic count (white arrow) Prominence and proliferation of lymphocytes in the mantle → Consistent with rapid growth of tumor zone that surrounds a small, atrophic germinal center PATHOLOGY Diseases of the WBC, Lymph Nodes & Spleen I Araceli P. Jacoba, MD, FPSP PAGE 10 of 18 PATHOLOGY | LE 2 Diseases of the WBC, Lymph Nodes & Spleen I | Araceli P. Jacoba, MD, FPSP Homogenous small lymphocytes without large cells resembling prolymphocytes (CLL) or centroblasts (follicular 💬 Lymphomas, leukemias are conditions wherein chromosome abnormalities are very significant the lymphoma) MARGINAL ZONE LYMPHOMA Tumors of Mucosa Associated Lymphoid Tissue 💬 One SUMMARY OF CLINICAL BEHAVIOR of the characteristics of this group of disorders is that each type of lymphoma will have its own clinical (MALToma) presentation. Characteristics: Table 5. Summary of Clinical Behavior → Arise from chronic inflammatory disorders (i.e., Age Group Clinical Feature Hashimoto's thyroiditis, PUD with H. pylori, Sjogrens SLL/CLL >60 y/o, males Indolent; Spill in blood disease) Affect → Tumor can remain localized for a long period of time BM, liver, spleen → Tumor can regress if inciting agent is removed Follicular Middle age Indolent, incurable ▪ It is important to treat chronic infection like cases of Lymphoma M=F Generalized H.pylori in gastric ulcers lymphadenopathy The characteristics suggest that this type of lymphoma arising in chronically inflamed tissue lie in a continuum DLBCL Elderly Rapidly growing mass (LN between reactive hyperplasia to full blown lymphoma. This Pedia or is the reason why H. pylori should be treated to prevent ExtraLN) occurrence of malignancy. Aggressive Prognosis: Burkitts Children Extranodal mass → This tumor as a whole has a very good prognosis, it is Aggressive important to identify factors that will cause it to behave Mantle Cell Older Males Disseminated Dis. otherwise. Aggressive → Poor prognostic factors for MALTomas, specifically a Marginal Any age MALTOMA BCL2 mutation t(11:18) or t(14:18) Zone ▪ When present, regression is not possible and Small Cell Lymphoma (SLL) 💬 transforms to more aggressive types of lymphoma → “Small” – gives a clue that tumor is indolent 💬 ▪ Specific for MALToma Older patients CHROMOSOMAL ABNORMALITIES IN LYMPHOMA Lymphocytes that grow in the lymph node goes to the Lymphoid tumors are characterized by chromosomal bone marrow and naturally spills into the blood abnormalities Table 4. Type of Lymphomas and its Chromosomal 💬 (similar to leukemia) SLL/CLL depends on the manifestation (more lymphocytes in peripheral blood = CLL; few Abnormalities. Type of ❗️ Chromosomes Function lymphocytes = SLL) Diffuse Large B cell lymphoma Lymphoma Involved → “Large” – gives a clue that tumor is aggressive Follicular Bcl 2-IgH t(14:18) Controls apoptosis Diffuse Large B-Cell Bcl-6 (30%) Bcl-2 (10%) Controls maturation Inhibit p53 💬 → Responsive to treatment Very aggressive tumors if left untreated Follicular lymphoma Cyclin D1-IgH Promotes G1 to S → “Follicles” – gives a clue that tumor is indolent Mantle Cell t(11:14) progression ▪ Normal nodes contains follicle Cause Warburg ▪ Cell of origin is Peripheral B. Burkitt’s C-myc loci t(8:14) effect ▪ Presence of follicles in this tumor: slow growing type The function of each chromosome abnormality and its contribution to neoplastic growth are identified. 💬 💬 of tumor Slow growing, can take several years Cannot be treated, “wait and see” wait for symptoms → Follicular lymphoma ▪ Bcl-2 - prevents apoptosis of the germinal center before treatment cells Marginal Zone − proliferation of lymphocytes in the germinal center → Mildest form of lymphoma arising from long standing → Diffuse Large B-Cell Lymphoma inflammation ▪ Bcl-6 inhibits expression of factors that promote → Can regress once inciting agent is removed germinal center B-cell to mature → produce cells in CELL ANTIGENS IN WBC undifferentiated proliferative state Table 6. Cell Antigens in WBC → Mantle Cell Lymphoma Type of Cells Antigens ▪ Cyclin D1 promotes rapid mitosis due to LCA CD 45 shortening the G1 phase with rapid progression to S T cell CD1, CD5, CD4/ CD8, CD3 phase B cell CD 10 - germinal center B, CD19, CD20 - → Burkitt’s Lymphoma pre B, mature B, CD23 - mature B, IgM - ▪ Warburg effect: C-MYC gene is a master plasma cells transcriptional regulator that alters metabolism to Monocyte/ CD11, CD13, CD14, CD15, CD33, CD64 allow cells to biosynthesize all building blocks macrophage (protein, nucleotide, lipid) for mitosis from just glucose and glutamine to allow for rapid growth and NK cell CD16, CD56 mitosis. This is the reason why cancer patients are Stem cell CD 34 cachectic. Hodgkins CD15, CD30 PATHOLOGY Diseases of the WBC, Lymph Nodes & Spleen I Araceli P. Jacoba, MD, FPSP PAGE 11 of 18  PATHOLOGY | LE 2 Diseases of the WBC, Lymph Nodes & Spleen I | Araceli P. Jacoba, MD, FPSP 💬 CD45 - present in all lymphoid tumors 2. PLAQUE PHASE 💬 Remember those in red: which are for monocytes. → will separate epithelial tumors from lymphoid tumors Elevation of the lesion from the skin surface Eczema like lesions raised above the skin forming B. PERIPHERAL T CELLS OR NK CELLS indurated, irregularly outlined, erythematous plaques that Review: may ulcerate → Precursor T/ Pre T cell Tumors - acute lymphoblastic lymphoma presenting as a mediastinal mass → Precursor B/ Pre B cell Tumors - reside in the bone marrow and presents as a leukemia Peripheral T Lymphomas are proliferating T lymphoblasts that have been released from the thymus and go to the parafollicular cells of the lymph node or to its normal location in other parts of the body. → T cell tumors are characterized by mass lesions at a particular location such as the skin or nasopharynx. (e.g. Mycosis Fungoides, Adult T Cell Lymphomas) → Those that present with lymphoma/leukemia are very aggressive tumors. rare 💬 Neoplasms of Peripheral T-Cells - all tumors are very → Mycosis Fungoides/ Sezary Syndrome ▪ Most commonly seen in the clinics → Extranodal NK/ T Cell lymphoma → Adult T cell Lymphoma/ Leukemia (CD4) Figure 27. Plaque stage of Mycosis Fungoides[Lecture PPT] → Anaplastic Large cell Lymphoma (ALK+) 3. TUMOR PHASE → Large Granular T-cell Lymphocytic Leukemia Lesion forms an enlarging mass/lesion on the skin MYCOSIS FUNGOIDES Malignant lymphocytes forms a bulging, tumoral mass Indolent tumors that are limited to the skin for long periods of time Infiltration of the skin by neoplastic CD4 T cells 💬 💬 instead of a flat, elevated lesion of the skin This stage is not seen in Sezary Syndrome Sezary syndrome: invades the circulation to cause Prognosis: Indolent; good splenomegaly, and lymphadenopathy and can invade → Localized to the skin for many years other organs as well 💬 → May evolve to systemic condition if left untreated Depends on the percentage of the body surface involved by the tumor Survival Rate (SR): 8 to 9 years MYCOSIS FUNGOIDES: CLINICAL STAGES OF CUTANEOUS LESIONS 1. INFLAMMATORY PHASE (PATCH STAGE) Flat-reddish patchy areas usually in the trunk Multiple, flat, map-like, reddish areas usually in the trunk Later progresses to involve the extremities Figure 28. Tumor stage of Mycosis Fungoides SEZARY SYNDROME Same histology as Mycosis Fungoides → Same CD4 lesion of the skin with infiltration of epidermis and dermis by malignant T cells Clinical picture: → Inflammatory and plaque phase only → Exfoliative erythroderma w/o tumor phase ▪ Reddish exfoliative patches that does not produce a mass, Instead of tumor proliferation that is limited to the skin forming a tumor phase − neoplastic lymphocytes enter the blood and spreads to the spleen and lymph node manifested Figure 26. Patch stage of Mycosis Fungoides[Lecture PPT] as lymphadenopathy and splenomegaly Prognosis: Aggressive (more aggressive than MF) PATHOLOGY Diseases of the WBC, Lymph Nodes & Spleen I Araceli P. Jacoba, MD, FPSP PAGE 12 of 18 PATHOLOGY | LE 2 Diseases of the WBC, Lymph Nodes & Spleen I | Araceli P. Jacoba, MD, FPSP HISTOLOGY: MYCOSIS FUNGOIDES & ADULT T-CELL LYMPHOMA / LEUKEMIA SEZARY SYNDROME CD4 T cell proliferation They have the same histologic features Caused: HTLV-1 Thick banned of atypical lymphocytes that aggregates in Signs and Symptoms: the superficial dermis with invasion of the epidermis seen → Skin lesions in single cell or small clusters ▪ Although it has a skin lesion, there will be more → Small clusters: Pautrier’s Microabscesses systemic manifestations because of a greater leukemic picture with a spread in circulation. → Hypercalcemia manifest as muscle weakness, renal (stones, polyuria), GIT (diarrhea, polydipsia) → General lymphadenopathy → Enlarged liver (hepatomegaly) and spleen (splenomegaly) → Blood lymphocytosis ▪ Indicating spillage in blood presenting as leukemia Etiology: This disease is the only malignancy established to be directly caused by a virus while others are only relationships. Morphology: Clover leaf or flower cells – multilobulated nuclei Complications: Demyelinating disease of brain and spinal cord Prognosis: Poor prognosis because it is highly aggressive and rapidly progressive Figure 29. Histology of Mycosis Fungoides & Sezary Syndrome showing Pautrier’s Microabscesses EXTRANODAL NK/T CELL LYMPHOMA T cell lymphoma of the sinuses & nasopharynx → T cell tumors usually involve a particular site of the body ▪ CD4 T-cell tumors: Skin ▪ NK cell tumor: Nasopharynx or sinuses Also called Lethal Midline Granuloma or Midline Malignant Reticulosis → Lethal: Characterizes the aggressiveness and destruction brought about by the tumor → Midline: Location in the nasopharynx and sinuses Figure 31. Adult T-Cell Lymphoma[Lecturer PPT] → Granuloma: Misnomer ▪ Extensive necrosis and the failure to find tumor cells C. HODGKIN'S LYMPHOMA wiped out by the necrosis was very typical for this When lymphocytes could not be identified by surface lesion markers as B or T, the whole classification of lymphoma is Symptoms: Destructive masses of sinus & nasopharynx divided only into 2 big groups: Hodgkins and non Morphology: Atypical lymphocytes invading small blood Hodgkin's Lymphoma vessels leading to necrosis and destruction of tissues Hodgkin's tumors are separated from the rest of the B → Histologic diagnosis will be difficult since it will only cell tumors because of a different behavior, prognosis, and show extensive necrosis despite multiple biopsies. histologic appearance. Associated with EBV First human cancer to be treated successfully with Prognosis: Aggressive radiotherapy & chemotherapy. → Respond to radiation but not to chemotherapy Lymphoid neoplasms containing neoplastic giant cells (Reed Sternberg Cells) that induce accumulation of other inflammatory cells. CHARACTERISTICS OF HODGKIN’S DISEASE Presence of RS cells → RS cells are surrounded by histiocytes, macrophages, eosinophils, fibroblasts, lymphocytes, and dendritic cells. All these cells work to feed and keep the RS cell 💬 alive. These cells also give tumor necrotic factors, transforming growth factors, and interleukin factors. 💬 Polymorphic cell Separates it from the other lymphomas outside of the RS cells Involve single axial lymph node chain Figure 30. Extranodal NK/T Cell Lymphoma[Lecture PPT] PATHOLOGY Diseases of the WBC, Lymph Nodes & Spleen I Araceli P. Jacoba, MD, FPSP PAGE 13 of 18 PATHOLOGY | LE 2 Diseases of the WBC, Lymph Nodes & Spleen I | Araceli P. Jacoba, MD, FPSP Spread is contiguous & stereotyped Table 9. Classification of Hodgkin's Lymphoma → Spread is in an orderly fashion CLASSIFICATION OF HODGKIN’S LYMPHOMA ▪ Spread is as follows: Nodes -> spleen -> liver -> Clinical bone marrow -> other tissues or organs Type Histology Prognosis Feature → Therefore when treated in the nodal stage, there is no Bands of M=F; Common Excellent risk of spread to other organs Nodular collagen in cervical and Stage 1-2 Rare extranodal presentation Sclerosis lacunar cells mediastinal, Table 7. Comparison of Hodgkins and Non-hodgkins (70%) young adults, HODGKIN’S NON-HODGKIN’S EBV- Spread in an orderly Spread jumps from one Many different M>F, EBV+ Good fashion area to the other Mixed cells, RS (70%) Affects multiple nodal Cellularity plentiful lymphadenopat Affects single nodal group (25%) hy, biphasic groups age Hodgkin's lymphoma is different in the sense that the RS Few Elderly males, Moderately cell are the tumor cells that release cytokines or Lymphocytic lymphocytes, HIV+, Most aggressive chemokines, inducing the accumulation of benign cells Depletion many RS & EBV+ like fibroblasts, monocytes, leukocyte to work for the tumor (5%) variants which is the RS cell. Many M>F middle Good to Only the RS cell is malignant while the other cells are lymphocytes, age males, enl excellent benign. Lymphocyte many RS LN, EBV+ Unlike other tumors, wherein the proliferating cells are all rich (40%) malignant. This simulates the queen in a beehive or ant colony that grows bigger and bigger as the other various Few RS/LH Young males, Very good ❗️ workers provide for all it seems. Lymphocytic variant of EBV- NO need to memorize the different signals or cytokines. predominance “popcorn” cell cervical/axillary Just be aware of this relationship between the RS and (5%) CD15 & CD30 lymphadenopat other inflammatory cells. negative hy Summary of the Subtypes of Hodgkin’s Lymphoma → The most important reason for sub classification is to determine prognosis and the histology. → As a whole, Hodgkin's lymphoma has a very good prognosis compared to other lymphomas of the same stage. → The prognosis parallels the amount of lymphocytes within the tumor ▪ Less lymphocytic cells = Poor Prognosis − Lymphocytic depletion ▪ More lymphocytic cells = Good Prognosis − Lymphocyte rich − Lymphocyte predominance − Nodular sclerosis means fibrosis of the tumor therefore, the prognosis is excellent (best) because the presence of collagen attempts to wipe out the tumor Figure 32. Mechanism involved in Hodgkin’s Lymphoma in → RS cells are abundant in most subtypes except in: relation to RS Cell [Lecturer’s PPT] ▪ Nodular sclerosis where it is replaced by lacunar cells CLASSIFICATION OF HODGKIN’S LYMPHOMA ▪ Lymphocytic predominance where it is replaced by Table 8. Classification of Hodgkin's Lymphoma popcorn cell 1. Nodular Sclerosis Classic Variants → EBV is common to all subtypes except: 2. Mixed Cellularity Positive for Hodgkin's ▪ Nodular sclerosis 3. Lymphocytic markers, CD 15 and CD 30 ▪ Lymphocytic predominance Depletion Negative for B cell markers → Commonly seen in HIV patients: ❗ 4. Lymphocyte rich despite it being B cells ▪ Lymphocytic depletion 5. Lymphocytic Non Classic Variants Need to memorize all five types because this is a predominance Negative for the Hodgkin’s high yield question in any board exam markers, CD 15 and CD 30 NODULAR SCLEROSIS Positive for B cell markers Nodular Sclerosis → Most common variant of Hodgkin's Lymphoma → It is characterized by collagen or fibrous bands of pink acellular tissue (black arrow) that separates lymph node into circumscribed tumor nodules → Grows into nodules separate by fibrous bands PATHOLOGY Diseases of the WBC, Lymph Nodes & Spleen I Araceli P. Jacoba, MD, FPSP PAGE 14 of 18 PATHOLOGY | LE 2 Diseases of the WBC, Lymph Nodes & Spleen I | Araceli P. Jacoba, MD, FPSP → Inset shows lacunar cells that replace the RS cells in this tumor → They are seen as large cells with clear space around the nuclei → Equal occurrence in males and females → Affect young adults → Very good prognosis ❗ → Positive markers: Classic type CD15 and CD30 Common board exam question Figure 35. Mixed Cellularity[Lecturer PPT] Figure 33. Nodular Sclerosis[Lecturer PPT] Figure 36. Mixed Cellularity[Lecturer PPT] LYMPHOCYTE RICH Lymphocyte Rich → Uncommon type of Hodgkin's Lymphoma → Reactive lymphocytes make up the vast majority of the infiltrate mixed with RS with less of the other cell types present in the tumor → Mononuclear cells and RS cells are common in this subtype → Males greater than Females → Tends to be seen in older adults → Good prognosis Figure 34. Nodular Sclerosis[Lecturer PPT] → Classical RS: Abundant lymphocytes ▪ +CD15, +CD30 MIXED CELLULARITY ▪ CD20 Mixed Cellularity → Second most common type of Hodgkin's Lymphoma → The involved node will have a heterogeneous infiltrate of T-lymphocyte, eosinophils, plasma cells, macrophages, abundance of diagnostic RS (black arrow) and some Lympho-histiocytic variants (red arrow). → Present in Stage III and Stage IV but remains to have a good prognosis → Males greater than females → Biphasic age incidence = young adults and older adults → Classical RS: ▪ +CD15, +CD30 ▪ - B & T cell marker ▪ - CD45 → Most are EBV positive Figure 37. Lymphocyte Rich[Lecturer PPT] PATHOLOGY Diseases of the WBC, Lymph Nodes & Spleen I Araceli P. Jacoba, MD, FPSP PAGE 15 of 18 PATHOLOGY | LE 2 Diseases of the WBC, Lymph Nodes & Spleen I | Araceli P. Jacoba, MD, FPSP LYMPHOCYTIC PREDOMINANCE → Large prominent nucleoli producing an “owl eye” appearance → Abundant cytoplasm → RS appears with plasma cells, dendritic cells, fibroblasts, monocytes/macrophages (larger paler cells) and T lymphocytes (small blue cells) → The T-lymphocytes are benign workers for the RS → The RS cell is the neoplastic B cell → RS should be distinguished from similar cells in IM, large cell NHL RS CELL VARIANTS Figure 38. Lymphocytic Predominance[Lecturer PPT] Lymphocytic Predominance → Uncommon type of Hodgkin's lymphoma. → Histologically similar to Lymphocyte Rich with a predominance of reactive lymphocytes. However, there will be two conditions that will differentiate this from your Lymphocyte Rich Lymphoma. ▪ First: Instead of the usual RS cell, there is an RS equivalent which appears as your lymphohistiocytic variant (black arrow) with cleaved or convoluted nuclei in the cells. ▪ Second: Immunohistochemistry Figure 40. RS Cell Variants. Left to Right: Lacunar, − Non-classical RS: Lymphohistiocytic, Mononuclear[Lecturer PPT] o - CD15, -CD30 Not all subtypes of Hodgkin's lymphoma will contain the o + B cell marker classic RS cells some may produce RS variants: o + CD20 → Lacunar cell → Seen mostly in young males ▪ Seen in nodular sclerosis REED STERNBERG (RS) CELLS ▪ Large cells with infolded nuclei located within a large empty space → Lymphohistiocytic variant or Popcorn cell ▪ Seen in lymphocytic predominance ▪ Large cells with cleavage or in folding of the nucleus → Mononuclear variant ▪ Large cell with an ink dot nucleoli So all of them are large cells that stand out in the histology of Hodgkin's lymphoma with varying nuclear and cytoplasmic characteristics. CD 15 IN CLASSIC HODGKINS Figure 39. Classic RS Cell[Lecturer’s PPT] RS cell is required for a diagnosis of Hodgkin's Lymphoma Hodgkin's lymphoma is based on the diagnosis of this RS cell in a background of non neoplastic inflammatory cells RS cells are the tumor cells in this lesion -> they release cytokines & chemokines -> inducing accumulation of benign inflammatory cells which in turn feed the RS Some infections may appear or contain RS like cells like Figure 41. CD 15 stain in Classic HL[Lecturer PPT] your infectious mononucleosis or some non-hodgkin's This is an immunostain for CD15 form of lymphoma. But the diagnosis of Hodgkins cannot Immunohistochemistry of Hodgkin's Lymphoma is Positive be made without the presence of this RS cells for CD 15 and CD 30 Reed Sternberg Cells Brown uptake is positive for CD 15 and present only in RS → Large binucleated or multinucleated cell that is a cells which are the tumor mirror image of each other PATHOLOGY Diseases of the WBC, Lymph Nodes & Spleen I Araceli P. Jacoba, MD, FPSP PAGE 16 of 18 PATHOLOGY | LE 2 Diseases of the WBC, Lymph Nodes & Spleen I | Araceli P. Jacoba, MD, FPSP None of the benign cells in background are positive for the cell surface. There will be independent proliferation & stain survival if the surface receptors are destroyed like PROGNOSIS OF HODGKIN'S LYMPHOMA what is seen in Polycythemia vera with destruction of the JAK pathway. Prognosis: Ann Arbor Classification: → Prognosis of Hodgkin's lymphoma as a whole is very → Determines the course and choice of therapy. good with a 5 year survival rate. → Very important in staging the course and determining ▪ Stage I & IIA - 5 year SR 90% the prognosis of this disease. ▪ Stage IVA & IVB – 5 year SR 70% Table 10. Ann Arbor Classification − For the early stages, Stage 1 and Stage 2 can achieve a cure rate of 90% Stage Characteristics − Those with disseminated diseases, 70% of cure 1 Only a single lymph node group or a single rate can be achieve extra nodal site involved → Even in the higher stages, the 5 year survival rate 2 Two or more lymph node sites on one side of remains high. This is due to the fact that the tumor cells the diaphragm are involved, or limited consist of only a few RS which can easily be destroyed contiguous extranodal site involvement by chemotherapy. It does not make up the whole of the 3 Lymph node sites on both sides of the tumor. The tumor is low, therefore is very low and easy diaphragm are involved, with splenic or limited to eradicate. contiguous extranodal involvement, or both → This is the first tumor ever successfully treated with 4 Extensive involvement of extranodal sites, with chemotherapy and radiotherapy. or without a lymph node involvement Complications of Chemotherapy and Radiation: All stages are further divided into the presence or absence → The only problem would be complications in patients' of the following symptoms either fever, night sweats or status post receiving chemotherapy or radiation. unexplained weight loss, more than 10% of normal body. → They may develop other forms of cancer like: V. SUMMARY ▪ AML (Acute Myeloid Leukemia) Reactive changes of WBC in blood & LN ▪ MDS (Myelodysplastic Syndrome) Lymphoid Neoplasms: WHO Classification of ▪ Lung Carcinoma Lymphoid Tumors Molecular Pathogenesis: → Precursor B cell (pre B cell) → Activation of transcription factor NF-kB by EBV or other ▪ B lymphoblastic Leu (ALL) / lymphoma mechanism stimulates mitosis in the nucleus. − Was not discuss bec