LECTURE LYMPHATIC AND HEMOPOETIC SYSTEM

Thomas Hodgkin 1798-1866 PRIMARY (CENTRAL) LYMPHATIC ORGANS – AND BURSA OF FABRITIUS SECONDARY – , LYMPH NODES, MUCOSA-ASSOCIATED LYMPHATIC TISSUE THYMIC-DEPENDENT LYMPHOCYTES T – CELLULAR IMMUNITY LYMPHOCYTES B – HUMORAL IMMUNITY

LYMPHOCYTES T IN NORMAL LYMPHOCYTES B IN . CD3 POSITIVE REACTION CENTROBLASTIC . CD20 POSITIVE REACTION THYMUS 1. DEVELOPMENTAL DISTURBANCES DI GEORGE SYNDROME (MICRODELETION 22q11) – AGENESIA OF 3RD AND 4TH BRANCHIAL POUCH – HYPOPLASIA OF THYMUS AND PARATHYROID; CONGENITAL HEART DEFECTS) 2. ATROPHY OF THYMUS; THYMITIS 3. THYMUS IN SYSTEMIC DISEASES (E.G. MYASTHENIA) 4. TUMORS -

LINING OF THE CYST – MULTILOCULAR CYST OF THYMUS SQUAMOUS EPITHELIUM TUMORS - THYMOMAS

THERE IS A NUMBER OF VARIOUS HISTOLOGICAL TYPES OF . LYMPHOCYTE-PREDOMINANT ENCAPSULATED, CYSTIC THYMOMA THYMOMA most common primary anterior mediastinal

• Ages 50+, occasionally children • Associated with hypercalcemia, elevated parathyroid hormone levels, pulmonary sarcoidosis • Not associated with paraneoplastic syndromes such as myasthenia gravis or pure red cell aplasia • Patients usually present with mass related symptoms • Aggressive clinical course • Usually cohesive cellular growth, regularly round / oval nuclear outlines, eosinophilic nucleoli, geographic necrosis LYMPH NODES REGRESSIVE CHANGES

LIPOMATOSIS, HYALINOSIS AND CALCIFICATIONS IN ANTHRACOSIS LYMPH NODES LYMPHONODULITIS

TYPES OF CELLS IN THE LYMPH NODE LYMPH NODES LYMPHONODULITIS

SUPPURATIVE (PURULENT) LYMPHONODULITIS REACTIVE LYMPHONODULITIS LYMPH NODE LYMPHONODULITIS

AIDS – MYCOTIC LYMPHONODULITIS CRYPTOCOCCUS NEOFORMANS SARCOIDOSIS LYMPH NODES METASTASES IN LYMPH NODES REMEMBER !!! LYMPH NODES ARE SITES OF METASTASES FROM MALIGNANT EPITHELIAL TUMORS IE. CARCINOMA

LYMPH NODE WITH METASTASES OF GASTRIC LYMPH NODES CLUSTERS WITH ADENOCARCINOMA (INITIAL PROLIFERATION IN METASTASES OF NASOPHARYNGEAL LYMPH NODE SINUSES) CARCINOMA SPLEEN • Congenital anomalies: • Accessory (supernumerary) spleen • (congenital absence of spleen) • Hepatolienal fusion • Hyposplenism: Atrophy of spleen with concomitant compromised splenic function. Usually acquired but rare congenital forms exist (isolated congenital hyposplenia, Ivemark syndrome, hypoparathyroidism syndrome, autoimmune polyendocrinopathy candidiasis ectodermal dystrophy [APECED] syndrome, Stormorken syndrome) • • SPLEEN REGRESSIVE CHANGES

GAUCHER DISEASE – ACCUMULATION OF LIPIDS IN MACROPHAGES IN SPLEEN

AMYLOIDOSIS IN SPLEEN GAUCHER DISEASE Bone marrow biopsy showing nodular aggregates of histiocytes, so-called Gaucher cells (upper left), among hematopoietic cells (lower right) (HE). Fig. 2.Bone marrow Gaucher cells, Fig. 3.Cut surface of FFPE specimen, showing multiple pale tan nodules, the largest with macroscopic necrosis. Fig. 4.Low-power histology of spleen with marginal zone and diffuse pattern of lymphomatous infiltrates within white and red pulp. Fig. 5.The large cells have pleomorphic nuclei with vesicular chromatin and prominent nuclei. Fig. 6.Splenic sinusoids are dilated and partially filled with Gaucher cells. The large cell lymphomatous infiltrate focally replaces the normal splenic tissue SPLEEN CIRCULATION DISTURBANCES

HEMOSIDEROSIS IN SPLEEN IN

CHRONIC VENOSTASIS SPLEEN

CYSTS

TUMORS

HEMANGIOMA CYSTS OF SPLEEN • Echinococcal cysts • Epithelial: Usually children or young adults; solitary or multiple; may be associated with • May mimic mucinous cystic neoplasm if in intrapancreatic accessory spleen; called "epithelioid" / "epidermoid" if squamous lining • Mesothelial: also called solitary splenic lymphangioma • may be due to trauma • Pseudocyst: 75% of nonparasitic splenic cysts; usually due to trauma; some may be epithelial cysts with denuded epithelial lining; usually solitary, asymptomatic BONE MARROW PATHOLOGY APLASIA AND HYPOPLASIA

NORMOBLASTIC BONE MARROW

BONE MARROW APLASIA IN A GIRL WITH SEVERE ANEMIA B.M. PATHOLOGY HYPERPLASIA – MYELOPROLIFERATIVE SYNDROMES

A. B.

NORMAL B.M. SMEAR (A) IN ACUTE LYMPHOBLASTIC LEUKEMIA (B)

A. B.

NORMAL B.M. SMEAR (A) IN ACUTE MYELOID LEUKEMIA (B) ACUTE LYMPHOBLASTIC LEUKEMIA (ALL) • May have widespread and hepatosplenomegaly at diagnosis • Nodal biopsies may be initial diagnostic procedure, although marrow involvement is usually present if tumor in node • May present as leukemia, lymphoma or both • Defined as leukemia if > 25% lymphoblasts in bone marrow or blood • Defined as lymphoma if mass lesion present in mediastinum or elsewhere and < 25% lymphoblasts in marrow and peripheral blood Acute myeloid leukemia / granulocytic sarcoma (AML) • Also called granulocytic / myeloid sarcoma or chloroma when it forms a mass; clonal neoplastic proliferation of hematopoietic precursor cells causing excessive myeloblasts and other immature myeloid cells • Diagnosis requires a high degree of suspicion; thin sections are needed to see cytoplasmic granules • Lymphadenopathy may be initial presentation, preceding marrow involvement by months or years • May present with nodal infarction Chronic Myeloid Myeloproliferative neoplasms (MPN) WHO classification of myeloproliferative neoplasms • Myeloproliferative neoplasms (MPN)

• Chronic myelogenous leukemia • Polycythemia vera • Essential thrombocythemia • Primary myelofibrosis • Chronic neutrophilic leukemia • Chronic eosinophilic leukemia, not otherwise categorized • Mast cell disease • MPNs, unclassifiable BONE MARROW PATHOLOGY MYELOPROLIFERATIVE SYNDROMES

B.M. IN MYELOID LEUKEMIA LEUKEMIC INFILTRATIONS IN SKIN

A. B.

NORMAL B.M. SMEAR (A) B.M. IN CHRONIC MYELOID LEUKEMIA (B) CHRONIC MYELOID LEUKEMIA • (CML) • Most common chronic myeloproliferative neoplasm • Incidence of 10 - 20 cases per million annually • All ages affected; median age in 5th - 6th decade • Originates from pluripotent stem cell that gives rise to myeloid and lymphoid cells • Marrow has neoplastic and normal granulocyte precursors; BCR- ABL identified in all myeloid lineages and some lymphoid cells and endothelial cells but clinically only affects granulocytes • Insidious onset with anemia, fatigue, weight loss; may have dragging sensation due to ; 20 – 40% are asymptomatic and diagnosed incidentally by WBC count • Extramedullary hematopoiesis may cause hepatosplenomegaly and lymphadenopathy; may have splenic infarcts BONE MARROW PATHOLOGY MYELOPROLIFERATIVE SYNDROMES

B.M. IN CHRONIC LYMPHOCYTIC LEUKEMIA POLYCYTHEMIA VERA, RUBRA

H & E MYELOFIBROSIS RETICULIN STAINING MYELOFIBROSIS • Myelofibrosis is an uncommon type of bone marrow that disrupts your body's normal production of blood cells. • Myelofibrosis causes extensive scarring in your bone marrow, leading to severe anemia that can cause weakness and fatigue. It can also cause a low number of blood-clotting cells called platelets, which increases the risk of bleeding. Myelofibrosis often causes an enlarged spleen. • Myelofibrosis is considered to be a chronic leukemia — a cancer that affects the blood-forming tissues in the body. Myelofibrosis belongs to a group of diseases called myeloproliferative disorders. • Some people with myelofibrosis have no symptoms and might not need treatment right away. Others with more-serious forms of the disease might need aggressive treatments right away. Treatment for myelofibrosis, which focuses on relieving symptoms, can involve a variety of options. TUMORS OF LYMPHATIC SYSTEM

DIFFERENT CLASSIFICATIONS

THE ROLE OF IMMUNOHISTOCHEMISTRY

LYMPHOCYTES B – CD20, CD 79a; LYMPHOCYTES T – CD 3, CD 43; PLASMA CELLS – CD 138; APOPTOSIS MARKER – BCL-2 (ANTI-APOPTOTIC); PROLIFERATION INDEX – Ki-67 B-CELL LYMPHOMA

DERIVED FROM NON-TUMOR PROGENITOR CELLS

A. Precursor cell tumors Centroblast Centrocyte a. Precursor B lymphoblastic leukemia/lymphoma. Macrophage B. Peripheral B cell tumors a. B-cell chronic lymphocytic leukemia/prolymphocytic leukemia/small lymphocytic lymphoma. b. Immunocytoma/lymphoplasmocytic lymphoma c. Mantle cell lymphoma d. Follicle centre lymphoma, follicular lymphoma e. Marginal zone B-cell lymphoma f. Hairy cell leukemia g. Plasmocytoma/plasma cell myeloma/multiple myeloma h. Diffuse large B-cell lymphoma i. Burkitt’s lymphoma LYMPHOBLASTIC LYMPHOMA/LEUKEMIA B CELL SMALL LYMPHOCYTIC LYMPHOMA

IMMUNOCYTOMA FOLLICLE CENTRE LYMPHOMA MARGINAL ZONE B CELL LYMPHOMA (MALT TYPE) HAIRY CELL LEUKEMIA

DIFFUSE LARGE B-CELL LYMPHOMA PLASMACYTOMA vs. MULTIPLE MYELOMA Plasmacytoma

• Solitary lesion of clonal plasma cells that are cytologically, immunophenotypically and genetically similar to plasma cell myeloma (multiple myeloma) • Solitary plasmacytoma of bone: localized bone tumor consisting of monoclonal plasma cells with no other radiographic lesions and no evidence of other bone marrow involvement; see also Bone chapter • Extraosseous (extramedullary) plasmacytoma: localized tumor of plasma cells (not in bone) Plasma cell myeloma (multiple myeloma)

• Bone marrow based, multifocal plasma cell neoplasm associated with a monoclonal immunoglobulin (M protein) in serum or urine • Diagnosis requires synthesis of clinical, laboratory, radiologic and histologic findings • Serum or urine M protein, clonal plasma cells in bone marrow and presence of end organ damage critical for diagnosis (especially if < 10% plasma cells or M protein levels below threshold) Plasma cell myeloma (multiple myeloma) • Often presents with bone pain, lytic bone lesions (thoracic vertebrae most common, also ribs, skull, , femur); spinal cord compression or peripheral neuropathy are less common presenting symptoms • Renal failure / elevated creatinine / hyperuricemia (renal tubular reabsorption of light chain results in damage); hypercalcemia; hypoalbuminemia; hyperviscosity in ~7% (usually IgA or IgG3) • Recurrent infections due to impaired humoral immunity (immunoglobulin production, often < 50% normal) including Streptococcus pneumoniae Staphylococcus aureus, E. coli Plasma cell myeloma (multiple myeloma) MULTIPLE MYELOMA – GROSS AND X-RAYS MULTIPLE MYELOMA

myweb1.lsbu.ac.uk/~dirt/m useum MULTIPLE MYELOMA

med.niigata-u.ac.jp BURKITT’S LYMPHOMA CHILDREN, ADULTS VERY RARE; STARRY SKY PATTERN; VERY AGGRESSIVE COURSE LYMPHOBLASTIC LYMPHOMA (LIVER)

LYMPHOBLASTIC LYMPHOMA (KIDNEY) T AND NK CELLS LYMPHOMA

A. Precursor cells: a. Precursor T lymphoblastic leukemia/lymphoma B. Peripheral T and NK cells: a. T-cell chronic lymphocytic leukemia/prolymphocytic leukemia/small lymphocytic lymphoma. b. Large granular lymphocyte leukemia (LGL) c. Mycosis fungoides/Sezary syndrome d. Peripheral T-cell , unspecified e. Angioimmunoblastic T-cell lymphoma (AILD) f. Angiocentric lymphoma g. Intestinal T-cell lymphoma h. Adult T-cell lymphoma/leukemia (ATL/L) i. Anaplastic large cell lymphoma (ALCL) T LYMPHOBLASTIC LYMPHOMA T LYMPHOCYTIC LYMPHOMA

LARGE GRANULAR LYMPHOCYTE LEUKEMIA PERIPHERAL T CELL LYMPHOMA MYCOSIS FUNGOIDES

PAUTRIER microabscess

COCOS ISLANDS

www.odyssei.com LYMPHOGRANULOMATOSIS MALIGNA (LGM) HODGKIN DISEASE; HODGKIN LYMPHOMA

HD – A LYMPHOMA, WITH REED-STERNBERG CELLS AND DIFFERENT TYPES OF INFLAMMATORY CELLS IN STROMA

THE STROMA IS POLYMORPHIC (IE. VARIOUS POPULATIONS OF CELLS ARE PRESENT)

HD - 40% OF ALL LYMPHOMAS. CLINICALLY: PAINFUL ENLARGEMENT OF MEDIASTINAL LYMPH NODES WITH FEVER, NIGHT SWEAT, LOSS OF WEIGHT, EXANTHEMA

SPLEEN, LIVER AND BONE MARROW ARE AFFECTED VIA BLOOD VESSELS; LYMPH NODES PER CONTINUITY LYMPHOGRANULOMATOSIS MALIGNA; HODGKIN DISEASE (HD)

GROSS PATHOLOGY OF LYMPH NODES IN HD LYMPHOGRANULOMATOSIS MALIGNA; HODGKIN DISEASE (HD)

HD INFILTRATIONS IN SPLEEN - „PEASANTS SAUSAGE” REED – STERNBERG CELLS (RS CELLS) THEY CONTAIN 2 - 3 NUCLEI AND A VERY DISTINCT NUCLEOLUS

BESIDE RS CELLS THERE ARE: LACUNAR CELLS IN NODULAR SCLEROSIS

CELLS IN HD ORIGINATE FROM REACTION CENTRES (B- LYMPHOCYTES) AND LESS OFTEN – T-LYMPHOCYTES) REMEMBER !!! Hodgkin’s lymphoma (disease) is a group of heterogenous tumors from B and T cells. It is not a nosological entity !

WHO CLASSIFICATION OF HD (2003) 1. LYMPHOCYTE PREDOMINANT – NODULAR TYPE LYMPHOCYTE PREDOMINANT – CLASSICAL TYPE 2. MIXED CELL TYPE 3. NODULAR SCLEROSIS 4. LYMPHOCYTE DEPLETION LYMPHOCYTE PREDOMINANT - NODULAR TYPE SLOW CLINICAL COURSE. NECK LYMPH NODES; LYMPHOCYTES ARE DOMINATING. LYMPHOCYTE PREDOMINANT – CLASSICAL TYPE VERY RARE TYPE; THE MAIN REASON OF MISDIAGNOSIS; SPLEEN, LIVER AND BONE MARROW ARE NOT AFFECTED; IN OLDER PATIENTS MIXED CELL TYPE THE MOST FREQUENT TYPE. TWO PEAKS OF OCCURRENCE: CHILDREN AND OLD PATIENTS. RS CELLS, HODGKIN CELLS, LYMPHOCYTES, PLASMA CELLS AND EOSINOPHILS NODULAR SCLEROSIS TYPE BESIDE MC THE MOST FREQUENT TYPE. YOUNG PEOPLE; NECK, SUPRA- AND INFRACLAVICULAR AND MEDIASTINAL LYMPH NODES

LACUNAR AND REED- STERNBERG CELLS

FIBROSIS OF LYMPH NODE RESULTS IN NODULAR STRUCTURE; LACUNAR CELLS ARE SEEN LYMPHOCYTE DEPLETION TYPE RELATIVELY RARE TYPE OF HODGKIN DISEASE (HD), IN OLDER PATIENTS, AGGRESSIVE COURSE WITH FEVER, PANCYTOPENIA, HEPATOSPLENOMEGALY, NECROSIS OF LYMPH NODES, ATYPICAL CELLS HOW TO SEND LYMPH NODES TO PATHOLOGY DEPARTMENT ? ✓EXCISE THEM IN ONE PIECE !!! ✓DO NOT FIX THEM ✓IF NOT DELIVERED AT ONCE – FIX THEM IN 4% BUFFERED FORMALIN ✓INCLUDE DETAILED CLINICAL DATA !!! THANK YOU