HematooncologyINSTITUTE OFPATHOLOGICALANATOMY

FM CU

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Overview

➢Hematopoetic tumors 1. basic characteristics of tumors2. classification3. tumor diagnostics

➢Case reports 1.- 2. case – leukemia3.- 4. case – lymphoma5.- 6. case – myeloproliferative disease7. case

➢Histologic slides – CML, CLL, Hodgkin lymphoma, DLBCL, plasmocytoma, mycosisfungoides, essential thrombocythemia

WHO classificationCELL ORIGIN

I. Myeloid neoplasia

II. Histiocytic neoplasia

III. Lymphocytic neoplasia

o Tumors from immature B-cells

(B lymfoblastic leukemia/lymphoma)

o Tumors from immature T-cells

(T lymfoblastic leukemia/lymphoma)

o Tumors from mature peripheral B-cells

o Tumors from mature peripheral T- and NK cells

o Hodgkin lymphoma

CLINICAL COURSE / CELLMATURATION

o Acute (blasic cells / rapidprogression)

o Chronic (mature cells / slowprogression)

Classifications▪ Classification based on the cell origin – myeloid or lymphoid

▪ Classification based on the clinical findings – solid or leukemia

HOWEVER! Some leukemias can grow in solid infiltrates in tissues/organs, and on the other hand, some solid hemopoetic tumors can turn intoleukemia and infiltrate various tissues diffusely

Leukemias vs. LymphomasLEUKEMIA

• Leukemia represents a heterogenous group of hemopoetic diseases that emergefrom a malignant proliferation of a certain line of hemopoesis / lymphopoesis.

• myeloid

• lymphoid

SOLID HEMOPOETIC TUMORS

▪ mainly tumors of lymphatictissues (lymph nodes + extranodallymphatic tissues)

Leukemia▪ includes bone marrow +/- peripheral blood

▪ can present as inconspicuous tissue infiltrate (e.g. skin – leukemia cutis)

▪ usually is classified as acute or chronic

▪ Acute = immature and more aggressive (blastic cells)

▪ Chronic = more differentiated phenotype and prolonged, slower course

▪ predmoinantly affects organs associated with extramedullary hemoposis

Lymphoma▪ tumorous mass, typically affecting lymphatic node

▪ clonal proliferation of lymphoid cells (T and B lymphocytes) in solid organs

▪ clinical manifestation: induration of lymph nodes without pain

▪ historic classification: HL and NHL

▪ classification based on affected tissues: nodal, extranodal, disseminated

▪ in areas with lymphatic tissue

▪ typical clinical course – B symptoms (wasting, night sweats, sub-febriletemperature)

Diagnostics of hemopoetic tumors• TNM staging can not be utilised

• grading varies for different types

• each nosologic unit is separate = has its own staging (solitary LN, groupof LN, infiltration of bone marrow, spleen, liver, other tissues, ...)

• presence / absence of B symptoms also affects the clinical classification

➢ indolent lymphomas (FL, MATL, B-CLL/SLL, MZL)

➢ aggressive lymphomas (BL, DLBCL)

Diagnostics of hemopoetic tumorso Basic examination – differential blood count

◦ Cytologic smear (blood, bone marrow)

◦ Cytogenetic and molecular-genetic examination

o Histology - LN biopsy (lymphomas)

- trepanobiopsy (myelopoetic tumors, lymphoma staging)

o IHC (immunophenotype) – B-cells CD20

– T-cells CD3, CD4, CD8

– plasma cells CD138, kappa and lamba Ig light chains

Summary

• Clonal proliferation of lymphocytes in solid organs = lymphoma

• Lymphomas arise from cells of lymphatic lineage (T, B, NK cells)

• Neoplastic proliferation of precursors of white blood cells in bone marrow or peripheral blood = leukemia

• Final diagnosis depends on the result of molecular-geneticexamination

• Each nosologic unit has its own staging

• Grading of hemopoetic tumors varies

• Based on the type of differentiation, they are divided intolymphoid and myeloid tumors

Case no.1

• 44-year-old male complains of a long lastingweakness. In physical examination an enlargedliver is dominant.

• Lab results: ↑↑WBC, ↓ activity of leukocyte alkaline phosphatase (LAP).

• Blood smear – numerous immaturegranulocytes

Chronic myeloid leukemiaCML• 20% of all leukemias, one of the most common leukemias in adults

•Etiology – gene translocation – Philadelphia chromosome (fusion gene BCR-ABL with a tyrosin-kinase activity)

•Lab findings: anemia, granulocytosis and immature cells (myeloblasts ≤ 5%)

•Biopsy – BM hypercellular, increased amount of myeloid precursor cells

• Clinical manifestation – mild fever, tiredness, night sweats, splenomegaly, hyperuricemia

• Clinical course:Chronic phase (blasts ≤ 10%)Accelerated phase (10 - 20% blasts)Blastic crisis (blasts ≥ 20%) – usually transformation into AML

Chronic myeloid leukemia (liver)

Chronic myeloid leukemia (liver)

Case no.2

• 67-year-old man complains of general tirednessand weakness, in the last 6 months he had several spontaneous nosebleeds.

• In physical examination the most dominantfinding is diffuse lymphadenopathy with mildhepatosplenomegaly.

Case no. 2

• Lab. findings: ↑↑↑ leukocytosis

•Peripheral blood smear – numerous smalllymphocytes

•Diff. blood count – lymphocytes 7500/ml

Chronic lymphocytic leukemiaCLL• neoplastic proliferation of small lymphocytes

• max. > 50 r., males

• etiology – chromosomal abnormalities

• biopsy – BM – infiltration by small lymphocytes

• Clinical manifestation – diffuse LAP, mucosal bleedings, tiredness, can havescarce symptoms

• duration – years / decades with chronic course (survival rate can be above 20y)

• B-CLL / B-SLL = the most common lymphocytic proliferation = most commonleukemia in adults

• T-CLL are rare

B-chronic lymphocytic leukemia (liver)

B-chronická lymfocytová leukémia (pečeň)

B-chronic lymphocytic leukemia (LN)

Case no. 3

•57-year-old male visited his general practicionerwith a continuously enlarging nodule on hisneck. He complains of weight loss and mildlyincreased temperature in the last 3 months.

•Physical examination revealed enlarged neckand inguinal lymph nodes without any pain, and hepatosplenomegaly.

•Laboratory results show mild anemia and increased LDH values.

DLBCL metastases to spleen and kidney

Diffuse large B-cell lymphomaNon-Hodgkin disease• most common type of NH B-lymphoma (approximately 35% of all NHL )

• frequent extranodal masses

• de novo or transformation from indolent lymphoma

• affects mainly older people (60), rare occurence in young adults and children ispossible

• typical rapid clinical course, B symptoms

➢ Clinical calssification based on cell origin:

1. proliferation of cells of germinal center (germinal center B-cell)

2. proliferation of postgerminal cells –worse prognosis (activated B-cell)

CD 20 CD 45

Case no. 4

• 22-year-old female visited her generalpractitioner with an enlarging, non-painfulnodule on her neck. In the last couple ofmonths she has been experiencing severe nightsweats and mildly increased body temperature. In the last 8 weeks she lost 7kg of weight.

• Physical examination reveals unilaterallymphadenopathy and splenomegaly.

• Bioptic examination reveals largemultinucleated cells with prominent nucleolithat resemble owl eyes.

Hodgkin lymphoma•Etiology – EBV infection

•bimodal age prevalence (20-30 years, above 50 years), primarly in LN (cervical LN), secondary extranodal infiltration

• Biopsy - LN - Reed-Sternberg cells CD30 +, CD15+ / Hodkin cells + non-tumor inflammatorycells.

• Clinical manifestation – non-painful LAP, pruritus, B symptoms.

• Good prognosis, however ,increased risk for secondary malignancies.

Histological featuers of HL• Reed-Sternberg cells: giant multinucleated cells

• owl-eyes cells: two prominent nucleoli, perinuclear halo

• lacunar cells: smaller, nucleus is in a lacuna due to cytoplasmic shrinkage

• popcorn cells: larger, multilobulated nucleus

• pleomorphic cells: pleomorphic, atypical nuclei

4. lymfocyte depleted

1. lymphocyte-rich 2. nodular sclerosis

3. mixed cellularity

CD30

CD3 (T-lymphocytes)

CD15

Case no. 5

•69-year-old male admitted to the hospital withdeteriorating pain of back and neck. He wasfeeling tired recently and was treated forurinary tract infection in the last 2 months.

• X-ray revealed a fracture of L2 and L3 and lyticbone lesions in the skull

• lab results showed anemia, increasedcreatinine, Bence-Jones protein in urine, hyperglobulinemia, azotemia.

• blood sedimentation was markedly increased

Plasmocytoma /Multiple myeloma• proliferation of monoclonal plasma cells producing IgG

• presence of the clone predispones biological behaviour of the myeloma alongwith clinical manifestation

• laboratory findings – Bence-Jones protein in urine, anemia, hypercalcemia, hyperglobulinemia

• majority of myelomas produce IgG and IgA

• low concentration of normal Ig = high rate of infections

➢ Macroscopically – solitary lesions, solitary bone, typically in orofacial region

➢ Clinical manifestation – bone pain and fractures, renal insufficiency, recurrentinfections, primary amyloidosis

• Ovoid shape

• Large, round nucleus

• Excentric nucleus

• Basophilic cytoplasm

• Golgi zone

• Radially arrangedchromatin

Case no. 6

• 29-year-old, physically active male with no previous medicalhistory was admitted to coronary unit with severe pain locatedprecordially, with profuse sweating lasting 30 minutes, withouta link to physical activity.

• non-smoker, in family history no signs of hyperlipidemia,diabetes mellitus, arterial hypertension or coronary arterydiseases

• during examination you find tachycardia (100/min), bloodpressure 130/80 mmHg, otherwise physical examination isnormal. ECG showed significant ST elevation in lower leadsindicating STEMI infarction. Blood examination for theenzymes of cardiac damage resulted positive. He wasprescribed aspirin with streptokinase for thrombolysis.

• he reponded well to treatment and was left without anyresidual symptoms

Essential thrombocythemia• myeloproliferative disease

• bone marrow disease characterised by increased proliferation of megakaryocytes in bone marrow

• overproduction of platelets can lead to increased rate of thrombusformation and hemorrhages

• ethiology is unknown

• can evolve into acute myeloid leukemia or myelofibrosis

• slow progressive disease with long asymptomatic periods alternatingwith periods of thrombotic or hemorrhagic events

Essential thrombocythemia - trepanobiopsy

Numerous giant atypical megakaryocytes with hyperlobulated nuclei

Clusters of atypical megakaryocytes

Case no. 7

• 60-year-old female farmer came to the hematology clinicwith generalised pruritus lasting for 3 years with mild loss offeeling in skin lasting for 5 years. On her back and both upperextremities she has numerous mixed hypo- and hyperpigmented maculopapular squamous spots

• she has no history of arthralgias, exposure to radiation or chemical substances, without edemas, bleeding into body cavities or other orifices

• without history of drug and substance abuse

• she was examined at dermatovenerology clinic, where evenleprosis was considered. She was being treated for long-termchronic dermatitis.

• examination at hematology clinic included full blood count, peripheral blood smear, chest x-ray, ultrasound abdominaland pelvic examination, renal and hepatic function tests. Allresults were normal

• other negative findings include virus antibody screening forHIV I and II, superficial Ag for hepatitis B and hepatitis C virus

Mycosis fungoides• the most common primary skin lymphoma

• indolent clinical course, just itchy skin – exanthematous pruritus

• mature T-cell lymphoma located in skin of middle aged, (mostly) men

Pathologic changes

•epidermal and dermal infiltration (epidermotropism)•primary dermal process•slow progress

Clinical stages• Premycotic stage (eczema, dermatitis) – macular• Stage of plaques• Stage of nodular tumors

✓Sezary syndrome: generalised erytrodermia, Sezary cells in blood, lymphadenopathy, hepatomegaly

Infiltration by T-lymphocytes, typical Pautier’s microabscesses in epidermis