V. Žampachová I. ÚP I. Pathology of the lymphatic and hematologic systems Lymph nodes ûNormal LN soft, nonpalpable ûLymphadenopathy – enlarged palpable LN ûTender LN – usually in acute reaction (hyperemia, edema of LN), commonly neck ûNontender LN – palpable firmer lump – mostly chronic reaction (neck LN, inguinal LN, …), chronic inflammation (TB, …), cancer ûPast medical history of the client important Lymph nodes û changes in size (˃10 mm), shape (fused together), consistency important, must be reported û ûLN in front or behind of ears, supraclavicular, pectoral – usually not affected by local inflammation – changes more suspicious û Disorders of the lymphatic system ûLymphadenitis – inflammation of LN û ûLymphadenopathy – reactive enlargement of LN (immune reaction) û ûLymphangitis – inflammation of lymphatic vessel û ûLymphedema – increased amount of lymph fluid in soft tissue Lymphadenopathy ûLN – defense barrier û ûRegional LN in focal infection /reaction, focal malignant tumor (reactive cervical lymphadenopathy in infection of oral cavity, pharynx, ears, head, skin or soft tissue û ûGeneralized lymphadenopathy - ≥ 2 groups of LN; in systemic infection, immunologic reaction, spread of a malignant tumor û Non-specific reactive lymphadenopathy nregional or systemic response of lymphatic tissue on antigenic stimulation (inflammation, tumor, foreign material) n nGross : acute lymphadenopathy (enlarged LN), hyperaemia, soft consistency, tender n nMicro: according to the cause – lymph. follicles activation and hyperplasia, sinus hyperplasia („histiocytosis“), T-zone activation Reactive lymphadenopathy •Reactive hyperplasia: ðFollicular (B) (bacteria, sterile inflammation) ðParacortical (T) ð(viruses, chronic inflammations) û •Sinus histiocytosis Norm_Anatom_Uzlina_Schem_Ioachim1994_1-3_Upr Follicular hyperplasia - reactive LU1, 100x.jpg Sinus histiocytosis Image057 Lymphadenitis ûAcute – LN region warm, reddened, LN enlarged, tender û ûUsually in more aggressive local infection, which affects even the LN (cervical in acute tonsillitis, inguinal in infection of extremities). Abscess possible. û ûShort duration (approx. 2 weeks), if the cause progresses → possible transformation into chronic lymphadenitis Lymphadenitis ûNon-specific: without specific microscopic patterns û ûSpecific: micro picture +/- specific for one cause – granulomatous inflammation (TB, sarcoidosis, mycotic infection,…) û ûChronic - LN enlarged, nontender, firmer ûLong duration, even persistent TBC lymphadenitis Image059 Tuberculosis ûTuberculous granuloma - basic morphology: û central caseous necrosis (soft), transformed epithelioid macrophages + multinucleated Langhans‘ giant cells (fusion of macrophages), rim of T-cells û ûMycobacterium tuberculosis Ziehl-Neelsen staining, acid-resistant bacteria TBC lymphadenitis Image061 Sarcoidosis ûChronic granulomatous inflammatory disease, direct etiology unknown û ûMostly in mediastinal LN, lung, skin, eye; any localisation possible û ûRegular small „tuberculoid“ granulomas without caseous necrosis Sarcoidosis ûMay be asymptomatic, chest X-ray: bilateral lymphadenopathy (diff. dg. x lymphoma, cancer metastasis) û ûSlow progression or remission + healing û û10% mortality (lung fibrosis, cor pulmonale), 20% lung or ocular dysfunction û Sarcoidosis Image062 Lymphangitis ûAcute inflammation of subcutaneous lymphatic vessels ûUsually from local wound/infection û ûRed streak under the skin („blood poisoning“) ûInvolved regional LN ûSystemic manifestation possible (fever, chills, malaise), bacteremia ûRisk of lymphedema Lymphedema ûSwelling of the soft tissues due to accumulation of protein-rich fluid in the extracellular space û ûCause: ↓ lymphatic transport capacity and/or increased amount of lymph û ûExtremities common; head, neck, abdomen, genitalia posssible Lymphedema ûPrimary (idiopathic): result of lymphatic maldevelopment, rare. ðMay be present at birth (connatal) ðCan develop later in life without known cause û ûSecondary (acquired) more common. ðResult of surgery, radiation, injury, trauma, scarring, or infection of the lymphatic system û Secondary lymphedema û ûSurgery: breast cancer, melanoma, prostate/bladder cancer, lymphoma, ovarian cancer, hip replacements ûRadiation therapy ûDrugs (steroid, etc.) ûTrauma – scarring, crush injury ûInfection: filariasis, etc. ûChronic venous insufficiency ûObesity ûSelf-induced û Lymphedema staging ûStage 0 – latent: reduced transport capacity, no edema present û ûStage I: pitting edema present, reversible (elevation) û ûStage II: nonpitting edema + fibrotic tissue, irreversible û ûStage III: lymphostatic elephantiasis, severe fibrotic edema, skin changes – folds, hyperkeratosis Lymphedema LymphedemaArm.jpg Lymphedema Lymphedema ûLymphedema is a disease. ûUntreated l. is progressive ûEarly diagnosis necessary ûIf fully evolved, no definitive cure possible. ûManagement strategies exist: treat the causing disorder; ûProteolysis, surgery, … ûLymphatic drainage – manual, compression bandage, pump Malignant complications ûAfter long-standing lymphedema possible evolution of malignant vessel tumor – angiosarcoma û ûSigns: reddish-blue and dark nodules, rapid growth, bleeding, ulceration ûBad prognosis Tissue changes in lymphedema ûHypoxemia, loss of functional cells ûProliferation of connective tissue cells (fibroblasts) ûProduction of collagen fibers ûFibrotic changes, sclerosis and induration ûFatty tissue increase û Hematopoiesis •from hematopoietic stem cell • •HSCs (Hematopoietic Stem Cells): pluripotent, ability of self-renewal (replication) • Þdue to asymetric cell division variable progenitor cells arise : •fenotypically identical cells – HSCs •fenotypically different cells – multipotent cells (progenitors of myeloid cell line or progenitors of lymhoid cell line) • •Regulation of hematopoiesis through specific growth factors • û û Hematopoetic stem cells • in BM (<0,1% of cells) Multipotent progenitors Multipotent progenitors Committed precursors Late precursors and mature forms •morphologically differentiated diferenciace krvinek.jpg Kumar et al.: Robbins&Cotran Pathologic Basis of Disease, 8th Edition. Possible signs of hematologic disorders ûCongestion ûInfarction ûThrombosis, embolism ûBleeding, bruising ûLymphadenopathy ûSplenomegaly ûFatigue, dyspnoea ûEdema: ðlymphedema ðcerebral edema ðinflammatory edema ðpulmonary edema Emergency disorder ûShock: acute circulatory failure causing hypoperfusion of vital organs ûCardiogenic or hypovolemic ðHypotension ðRapid, weak pulse ðPallor ðMoist, cooler skin ðBleeding foci possible, if shock due to bacterial toxemia (pinpoint bleeding into the skin) Shock ûIschemic injury of multiple organs ûSerious clinical problem, commonly fatal ûConsequences: ðRenal failure ðAcute pancreatitis ðIrreversible neuronal injury, risk of cerebral infarction ðRisk of myocardial infarction ðLung insufficiency – acute respiratory distress syndrome ð ðMultiorgan failure (MOF) possible ð ð Hematologic disorders ûAlteration of the oxygen-carrying capacity of the blood ûChanges of the structure, consistency of the blood ûAlteration of the blood flow û ûIncreased workload of the heart and/or lungs ûAlteration of tissue perfusion ûIncreased risk of thrombosis ûIncreased risk of bleeding û ûModifications of therapy according to the blood + other tests necessary Disorders of erythrocytes (RBC) ûAnaemia ûReduction of the oxygen-carrying capacity of the blood due to decreased quantity and/or quality of RBC ûPosthemorrhagic: trauma, cancer (GIT, urinary, genital, lung), ulcers, varices, coagulopathy… ûHemolytic (destruction of RBC): mechanical (artificial heart valve), autoimmune, inborn defects (of hemoglobin etc.), infection (malaria), hypersplenism ûDecreased production of RBC: nutritional deficiency; bone marrow failure – due to neoplasia, drugs (antineoplastic), endocrine disorders; chronic diseases – anaemia of inflammation û û Implications for the therapist ûDiminished exercise tolerance + easy fatigability ûCombination with other problems common (cardiovascular, renal, …) ûRisk of combination with bleeding disorders - !manual therapy ûImpaired healing of wounds ûMonitoring of vital signs and mental status necessary ûIn young athletic clients iron-deficiency anemia possible (females, dietary choices, drugs, etc.) Disorders of leukocytes ûLeukocytosis û↑ number of WBC, usually of specific group ûAcute haemorrhage (after 1-2 hrs) ûInfection (mostly bacterial for neutrophils, viral for lymphocytes) ûInflammatory reaction in tissue necrosis, trauma ûImmune-mediated disorders (incl. allergic reaction – eosinophils) ûMalignancies, incl. hematologic ûReaction to stress, incl. exercise û Disorders of leukocytes ûLeukopenia û↓number of WBC (≤5000/ml) ûInfection (HIV, other viruses – destruction of WBC) ûAlcohol ûNutritional status ûDrugs (antineoplastic, immunosuppressive, NSAID, antibiotic) ûMalignancies incl. hematologic, carcinomas ûRadiation therapy Implications for the therapist ûImmune deficiency – risk of infection! Disorders of hemostasis ûVon Willebrand disease – problems in formation of the primary platelet plug ûHemophilia – lack of clotting factor for secondary hemostasis; arthropathy, spontaneous bleeding, major bleeding after minor trauma ûAcquired coagulopathy – common due to therapy (aspirin, antithrombotic drugs) ûThrombocytopenia / thrombocytopathy – mucosal bleeding common, easy bruising, heavy menstruation bleeding, GIT bleeding û Implications for the therapist ûIndividual exercise planning according to the client stage TUMORS of HAEMATOPOETIC and LYMPHATIC TISSUES ûBroad spectrum of entities û WHO classification - clinical, morphologic, imunophenotypic and genetic features defining distinct diseases. Etiopathogenesis of hematooncological diseases •??? • •hereditary syndromes •Inherited genetic instability (Bloom´s sy, ataxia teleangiectasia…), Down´s sy, NF type I… • •oncogenic viruses •HTLV-1, EBV, HSV-8 • •chronic stimulation of immune system •Helicobacter pylori, gluten-sensitive enteropathy (celiac sprue) • •iatrogenicity •radiotherapy, chemotherapy • •smoking û Hematooncology •Leukemia (hemoblastosis) •Diffuse replacement of normal BM by leukemic cells with their subsequent variable accumulation in peripheral blood (=leukemization) • •Infiltration of peripheral organs (liver, spleen, lymph nodes, meninges, gonads,….), tissue infiltration → organ enlargement without solid foci. • û Hematooncology •Lymphoma (hemoblastoma) •Neoplastic/lymphoma cells form tumor/neoplastic mass (nodal and/or extranodal) •solid tumorous foci, dissemination in form of metastasis. Usually lymphoid origin, rare histiocytic ð !Lymphomas may also present by leukemic infiltrates and leukemias also form solid neoplastic massess û Hematooncological diseases classification û Myeloid neoplasms -Monoclonal proliferations from stem cells that normally give rise to the formed blood elements -Replacement of normal bone marrow -3 categories û → acute myelogenous leukemias û → myeloproliferative disorders û → myelodysplastic syndromes û û Lymphoid neoplasms û→ non-Hodgkin lymphomas û(incl. lymphocytic leukemias and plasma cell dyskrasias) û→ Hodgkin lymphomas û û Histiocytic neoplasms Hematooncology ûMyeloid neoplasms ûCells of the myeloid line û (erythrocytes, granulocytes, monocytes, platelets) û ûPrimary involvement of bone marrow û (secondary spleen, liver and lymph nodes) Hematooncology ûGeneral clinical signs in acute leukaemia û rapid onset; marrow failure → ûAnaemia (fatigue, dyspnea, palor) ûNeutropenia (bacterial, fungal infection – fever, repeated oral/respiratory inflammation), ûThrombocytopenia (bleeding, epistaxis, haematomas) û ûWeight loss (increased cell turn-over) ûHepatomegaly, splenomegaly (compression of adjacent organs) û Hematooncology ûAcute myeloid (myeloblastic) leukaemia ûprimarily in older adults (median age 50), incidence rises with age ûleukemic infiltrates in bone marrow, liver, spleen, lymph nodes ûpossible solid tumor manifestation (myeloid sarcoma) ûgenerally poor prognosis û û Hematooncology ûMyelodysplastic syndromes: clonal stem cell disorders, ineffective haematopoesis→ cytopenias; dysplastic maturation. De novo or after radio/chemotherapy. Progressive marrow failure. May → AML. û ûMyelodysplastic/myeloproliferative diseases overlapping features, variably effective haematopoesis, dysplasia û Hematooncology ûChronic myeloproliferative diseases clonal stem cell disorders – hypercellular marrow with maturation, no dysplasia, effective haematopoesis → elevated blood levels of one or more cell lines, usually hepatosplenomegaly, lymphadenopathy û ûchronic myeloid (myelogenous) leukaemia ûessential thrombocythaemia û polycythaemia vera (rubra) (RBC) ûchronic idiopatic myelofibrosis Chronic myelogenous leukemia ûadults, peak incidence in 4th and 5th decade ûelevated leukocyte count û15-20% all leukaemias ûhuge spleen (~5-7 kg), liver enlargement ûclinical picture: anemia, hypermetabolism due to increased cell turnover: fatigability, weakness, weight loss, anorexia…..slow progression-accelerated phase - blastic crisis (AML-like) ûpoor prognosis; ûtherapy: transplantation of bone marrow, specific drug available û û CML in the liver Image065 CML – splenomegaly, spine infitrates Image066 Implications for the therapist ûLeukemia ûProblems due to neoplasia + therapy ûImmune deficiency – risk of infection! ûThrombocytopenia – bleeding ûAnaemia ûOther possible side effects of therapy (mood changes; muscle weakness in corticosteroid therapy) ûJoint problems (arthralgia, arthritis) û ûExercise necessary for improvement in health-related quality of life, mental health, reduced symptoms û Hematooncology ûHistiocytic and dendritic cell neoplasms ûfrom mononuclear phagocytes – common bone marrow precursor ûfollicular dendritic cells non-myeloid, from mesenchymal stem cell û ûtrue histiocytic neoplasm uncommon (Langerhans cell histiocytosis) û Non-Hodgkin lymphomas/ WHO classification Peripheral T-/NK-Cell Neoplasms Peripheral B-Cell Neoplasms Precursor T-Cell Neoplasms - precursor T-cell leukemia/lymphoma (T-cell acute lymphoblastic leukemia) Precursor B-Cell Neoplasms - precursor B-cell leukemia/lymphoma (B-cell acute lymphoblastic leukemia) T-Cell Neoplasms B-Cell Neoplasms Nodal lymphomas different cell type/stage of immunologic maturation → different lymphoma type û Norm_Anatom_Uzlina_Schem_Ioachim1994_1-3_Upr Marginal zone FL→DLBCL Burkitt MCL CLL DLBCL Peripheral T-cell ALCL. T- B- Angioimmunoblastic B-cell acute lymphoblastic leukemia/lymphoma (B-ALL) •most frequent malignancy in children û (peak at age 4) • •Infiltration of bone marrow, lymph nodes, liver, spleen… • •Highly aggressive, but chemosensitive û (Þ children 2 to 10 years – best prognosis) ðchemo-, radiotherapy generally carcinogenic in itself ð! increased risk of secondary malignancy (other type of leukemia/lymphoma, lung cancer, etc.) after several years - decades û û Peripheral B-cell lymphomas (selected) ûChronic lymphocytic leukemia / small cell lymphoma ûFollicular lymphoma ûMALT lymphoma ûPlasma cell neoplasms ûDiffuse large B-cell lymphoma Chronic lymphocytic leukemia (CLL) ûMature B-cell neoplasm, same cellular morphology and genotype in small lymphocytic lymphoma (in CLL lymphocytosis in peripheral blood) û ûMost common chronic leukaemia, common protracted course (~10 yrs), in >50 yrs old. Possible transformation to high grade ML û ûHypercellular bone marrow, generalised lymphadenopathy, hepatosplenomegaly CLL- hepatic and nodal infiltrates Image069 Follicular lymphoma ûMature B-cell non-Hodgkin lymphoma; ûcommon type (40%) û ûNeoplasia of follicle centre B-cells In LN - predominantly follicular pattern, sm. diffuse. May be in spleen, Waldeyer‘s ring,… Follicular lymphoma ûClinically: nontender generalised lymphadenopathy, commonly widespread disease at diagnosis (incl. liver, bone marrow), middle → late age adults. û ûLow grade – longer course (5-10 years), usually incurable ûHigh grade – aggressive, potential for cure (remission), but possible transformation into diffuse large B-cell lymphoma û Spleen, follicular lymphoma Extranodal marginal zone lymphoma (MALT lymphoma) •derived from mucosa-associated lymphatic tissue (salivary glands, thyroid, stomach, intestine, …) •chronic stimulation of immune system •e.g.: chronic gastritis associated with Helicobacter pylori (HP) infection •some autoimmune inflammations (thyroiditis, salivary glands, ...) • •low grade/aggressive lymphoma û û Diffuse large B-cell lymphoma (DLBCL) û •older adults, most frequent lymphoma • •highly aggressive • •de novo or high grade transformation of low grade lymphoma (CLL, FL, MALToma…) • •nodal or extranodal (tonsil, adenoid lymphatic tissue, GIT, skin, bones, thyroid, …) Plasma cell neoplasms ûIncluded in mature B cell neoplasms, clonal prolif. of immunoglobulin secreting end-stage B cell. Most common plasma cell (multiple) myeloma û ûBone marrow-based, multifocal, in older adults, destructive skeletal (osteolytic) lesion, common in foci of active haematopoesis (vertebrae, ribs, skull, …) ûPathological fractures, hypercalcaemia, anaemia ûRenal complications û Multiple myeloma in skull Image073 Multiple myeloma in skull – X-ray prostřílená kalva Multiple myeloma in spine Image074 T-cell lymphomas (selected entities) •Generally uncommon •Possible origin in the skin •unusual chronic relapsing „dermatitis“ • •Mycosis fungoides/Sézary syndrome •MF: Primary skin lymphoma •SS: leukemized, erythroderma • •Anaplastic large cell lymphoma • û û Hodgkin lymphoma ûOne of most common malignancies in young adults û ûNon-tender lymhadenopathy (origin in LN), commonly cervical or axillary; usually localised at presentation (1-2 LN groups); in 30% systemic signs (high fever, night sweats, weight loss) û ûContinual spread from one group of LN to the next one, diaphragm important barrier for staging, late extralymphatic spread û Differences between HL and NHL Hodgkin lymphoma Non-Hodgkin Lymphoma Usually localized to a single axial group of LN (cervical, mediastinal, para-aortic) Involvement of multiple peripheral LN Contiguous spreading Non-contiguous spreading Mesenteric LN and Waldeyer ring rarely involved …… commonly involved Extranodal rare Extranodal common Diagnostic (neoplastic) cells admixed with reactive non-malignant inflammatory cells Neoplastic/lymphoma cells dominate B-cell origin B- or T-cell origin Hodgkin lymphoma û2 distinctive disease entities: ûNodular lymphocyte predominant HL: 80% males, 30-50 yrs, large neoplastic „popcorn, L&H“B cells among non-neoplastic ly û ûMostly localised at presentation, late relapse or transformation into DLBCL possible û ûStage I+II – 10 year survival in 80% Hodgkin lymphoma ûclassical Hodgkin lymphoma 95% of HL, 1. peak 15-35 yrs, 2. elderly; risk factor EBV; 75% in cervical LN û û4. subtypes ûvariable types/numbers of neoplastic Reed-Sternberg cells in the infiltrate ûRT, CHT → excellent prognosis, but risk of secondary malignancies (myelodysplastic sy, acute myeloblastic leukemia, lung ca) û û Diagnostic cells of HL Sternberg c. copy Reed-Sternberg c. L&H c. Lacunar c. Hodgkin c. Hodgkin lymphoma – splenic infiltrates Image086 Implications for the therapist ûLymphadenopathy (diagnosis) ûInfection control ûMobility + gait training ûAerobic conditioning ûRespiratory rehabilitation ûLymphedema management ûSpecial management in multiple myeloma: muscle wasting, risk of pathological fractures