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Lymphoreticular Pathology (Primary Neoplasms: Lymphomas Malignancies…
Lymphoreticular Pathology
Non-neoplastic Pathology
1. Infections
Acute non-specific lymphadenitis: Staphylococcus
Granulomatous:
Mycobacterium
Fungal infection
Cat-scratch
Lymphogranuloma Venereum
Sarcoidosis
Viral
EBV (infectious mononucleosis)
2. Necrotising Lymphadenitis
Kikuchi's Lymphadenitis
Commonly seen in young female patients
3. Drug-related Lymphadenopathy
Anticonvulsants, phenytoin
May be mistaken to be lymphomas
4. Autoimmune Diseases
Rheumatoid arthritis
SLE
Primary Neoplasms: Lymphomas
Malignancies
of the lymphoid system which primarily manifests themselves
outside the bone marrow
, at sites of normal lymphoid homing (LNs, spleen, thymus, MALT)
Hodgkin Lymphoma (7%)
Classical (95%)
Features:
Lymphoid neoplasm composed of
Reed-Sternberg cells (neoplastic altered B cell)
residing in an
inflammatory (non-neoplastic)
background, including lymphocytes, histiocytes, eosinophils and plasma cells
CD15+, CD30+
Negative for other B cell markers and CD45 (leukocyte common antigen)
Spread by anatomical contiguity
4 types:
Nodular sclerosis, Mixed cellularity, Lymphocyte rich, Lymphocyte depleted
Clinical:
Painless lymphadenopathy
B symptoms (more so for stage III-IV or mixed cellularity and lymphocyte depleted subtypes)
Treatment:
Limited stage, low bulk disease treated with radiation therapy
Higher stage disease with B symptoms (stage IIB-IV) treated with multi-agent chemotherapy and radiation therapy (but this predisposes to other malignancies)
Overall cure rate = 80%
Nodular lymphocyte predominant Hodgkin Lymphoma (5%)
Non-Hodgkin Lymphoma (93%)
NHL is 5th most common cancer in males, 7th in females
B cell Lymphomas (88%)
Immature/Precursor B cell (lymphoblastic, <1%)
2. Mature B cell lymphomas (majority >87%)
AGGRESSIVE
1. Diffuse Large B Cell Lymphoma (31%)
Clinical:
Most common NHL
Disease of adults and children (median age 64)
Presents with rapidly enlarging masses
~40% curable with aggressive chemotherapy/stem cell transplant
Pathogenesis:
Several cytologic abnormalities but no defining one
Morphology:
Diffuse infiltration of LN, large lymphoid cells
Surface antigens:
B-cell markers + (eg. CD20+)
2. Mantle Cell Lymphoma (6%)
t(11;14)
Cyclin D1
IgH
3. Burkitt Lymphoma (3%)
Clinical:
Disease of adults and children (median age 31)
Asc wit EBV
Localisation in jaw
1/3 of all childhood lymphomas
Pathogenesis:
t(8;14) producing up regulation of MYC oncogene - cell cycle regulation gene
Morphology:
Diffuse infiltration of LN
High cell turnover --> attracts macrophages to phagocytose --> starry sky pattern at low power
Surface antigens: CD10, CD20
4. Mediastinal large B-cell lymphoma (2%)
INDOLENT
1. Follicular Lymphoma (22%)
Clinical:
Most common type of indolent lymphoma in US
Second most
common lymphoma overall
Disease of adults > 40 (median age 59)
Usu
widely disseminated
at diagnosis, incl bone marrow
Will respond to gentle chemotherapy but will relapse
Incurable short of bone marrow transplant, unless rare limited disease
Overall 5 year survival 72%
Pathogenesis:
t(14;18) (q32, q21)
Upregulates expression of an
anti-apoptotic protein Bcl2
Immortalises lymphoma cells
Morphology:
Retain characteristic follicular structure, but monotonous accumulation of single cell type
Surface antigens:
Characteristic immunophenotype CD10,CD20,Bcl2
Molecular signature:
Detect translocation by cytogenetics, FISH and/or PCR
Small lymphocytic lymphoma
Marginal zone lymphoma
Splenic, extra nodal, nodal
T and NK cell lymphomas (12%)
1. Immature/Precursor T cell (lymphoblastic, 2%)
Aggressive
2. Mature/Peripheral T cell lymphoma (10%)
Aggressive:
1. Peripheral T cell lymphoma NOS (4%)
2. Anaplastic large cell lymphoma (2%)
t(2;5)
NPM
ALK
3. Extranodal Nasal NK/T cell lymphoma (1%)
Clinical Presentation:
Enlarging masses at sites of nodal tissue
Typically painless
Hollow organs compression/infiltration
Pain, obstruction, perforation
Solid organ infiltration
Kidneys-, liver-, bone marrow insufficiency
Systemic symptoms
Fever
Night sweats
Weight loss (>10% body weight)
Aggressive vs. Indolent
Aggressive
Accelerated replication (defective cell cycle control)
Often more
*localised
than indolent
Shorter natural history
Median survival </= 2 years
Curable with aggressive therapy
Approx 30-40% of adults
50-80% of children
All childhood lymphomas are of this type
Indolent
Replicate at a very slow rate (slow accumulation due to defective apoptosis)
Often more widespread at diagnosis
Prolonged natural history
Median survival > 5 years
Current
incurable
unless
Localised disease
or
Marrow ablation with some type of stem cell transplant
Pathological Diagnosis of Lymphoma
Clinical Features
Primary site
Stomach, thyroid, lung: MALT lymphoma
Mediastinum:
Adult:
Classical HL
Large B cell lymphoma
Children:
Precursor T-lymphoblastic lymphoma
Immune deficiency conditions:
HIV+ patients: Burkitt Lymphoma
Transplant patients: Post-transplant lymphoproliferative disorders
Infections
EBV: Burkitt Lymphoma, Classical HL
H. pylori: MALT lymphoma of stomach
Morphology:
Disruption of normal LN architecture
Growth pattern:
Diffuse: DLBCL
Nodular: Follicular lymphoma
Lymphoma cell size:
Large cells: DLBCL
Small cells: FL, mantle cell lymphoma
Mixed: HL, T-cell lymphoma
Specific characteristic subtypes:
eg. Starry sky appearance in BL
Surface antigens expression:
Methods of detection: Immunochemistry, flow cytometry
Markers indicating cell of origin/lineage:
B-cell markers: CD20
T cell markers: CD3
Markers characteristic of specific subtypes of lymphoma:
Follicular lymphoma and Burkitt lymphoma: Follicle centre markers + (CD10, BCL6)
Classic HL lymphoma: CD30+, CD15+
Markers of specific molecular abnormalities in specific subtypes:
Follicular lymphoma: bcl2+
Mantle cell lymphoma: cyclin D1+
Burkitt lymphoma: Ki67 proliferation 100%
Molecular Signatures
Follicular Lymphoma
t(14;18) (q32;21)
BCL-2
up regulation- Transcriptional factor regulating B-cell proliferation and differentiation
Burkitt Lymphoma
t(8;14) (q24;q32)
C-MYC
up regulation - Transcription factor regulating cell proliferation and growth
Mantle Cell Lymphoma
t(11;14) (q13;q32)
BCL-1 or CyclinD1
up regulation - Cell cycle regulator
ALK+ Anaplastic Large Cell Lymphoma
t(2;5) (p23;q35)
ALK
up regulation - Tyrosine kinase, normal functions unknown. Upregulation of ALK --> deregulation of cell growth and apoptosis
Practical Approach to LN Enlargement
Suspect lymphoma
FNAC
Biopsy
Send fresh specimens
Flow cytometry (fresh)
Histology
Immunochemistry
Cytogenetics (fresh)
Detect diagnostic translocations
Molecular tests (+/- fresh)
eg. clonality test using PCR
Suspect infection
FNAC
Biopsy
Culture
Serology
Leukemias
Malignancies of the
hematopoietic
system which are primarily disorders of the bone marrow
Presenting with widespread involvement of the bone marrow
No discrete tumour mass is formed
Usually with large numbers of tumour cells circulating in the peripheral blood
Progression
Leukemic cells originate within the bone marrow
Usually overgrows the normal bone marrow cells
Replaces normal hypercellularity with monotony (1 predominant neoplastic cell type)
Leukemic cells usually spill from the bone marrow into the blood, where they may be seen in large numbers
Leukemic cells may also infiltrate lymph nodes, liver, spleen and other tissues, causing secondary organomegaly
3 main hematopoietic cell lines
(40-70% volume)
Erythroid series - Erythrocytes
Myeloid series - Polymorphs
Megakaryocytic series - Platelets
Other cell types: Lymphocytes, plasma cells, etc
Acute vs Chronic
Acute Leukemia:
Usually appear with symptoms resulting from
suppression of normal marrow function
:
Anemia, with accompanying fatigue
Fever and infection (due to leukocytopenia)
Bleeding, usually caused by thrombocytopenia
Acute leukemias are usually fatal within weeks if left untreated
Characterised by presence of immature, blast cells
Chronic Leukemia:
Can appear with
non-specific
symptoms
Fatigue
Weight loss
Anemia
Abnormal sensation in the abdomen caused by splenomegaly
Patients with untreated chronic leukemias usually survive much longer
Usually associated with more mature and well-differentiated cells
1. Acute Lymphoblastic Leukaemia (ALL)
Rare
Most common cancer of children
, with a peak incidence at age 3
2. Acute Myelogenous Leukemia (AML)
Rapidly fatal without treatment
More common in adults than children
3. Chronic Lymphocytic Leukemia (CLL)
Represent approx
1/3 of all leukemias
CLL is primarily a disease of the
elderly
, median age of onset = 55 years
4. Chronic Myelogenous Leukemia (CML)
Usually a disease of middle age, although it may occur in children and young adults
Usually presents in an
indolent chronic phase
(4-6 years)
The disease invariably progresses from the chronic phase to an accelerated and acute (plastic) phase, lasting 0.5 to 2 years
Philadelphia chromosome t(9;22), encodes BCR-ABL chimeric tyrosine kinase
Can treat with
imatinib mesylate
(a tyrosine kinase inhibitor)
Pathological Diagnosis
Clinical:
Abnormal blood counts
Signs and symptoms
Sites of involvement
Morphology:
Certain morphological features of leukemias
Surface antigens:
Certain antibodies
Molecular signatures
Certain DNA alterations, usually translocations
Thymus Pathology
2. Non-neoplastic Conditions
Thymic Hyperplasia
Myasthenia Gravis
Autoantibodies acting as competitive antagonists produced against acetylcholine receptors in neuromuscular junction
Asc with thymomas
3. Thymic (mediastinal) Neoplasms
Children (1% of all cancers)
43% NHL
28% HL
16% Neuroblastomas
10% Germ cell tumours
2% misc
Adults (<1% of all cancers)
25% Thymomas
20% Lymphomas
10-15% Germ cell tumours
10% Neurogenic tumours
30% misc
Benign thymoma
Cytologically benign
Clinically benign
Malignant thymoma type 1
Cytologically benign
Clinically malignant
Malignant thymoma type II
Cytologically malignant
Clinically malignant
1. Developmental Disorders
Thymic Hypoplasia
Seen in DiGeorge syndrome
Results in severe defects in cell-mediated immunity
Asc with variable abnormalities in parathyroid gland development
Spleen Pathology
Functions
Filtration of unwanted elements of the blood
Major secondary organ in the immune system
Source of lymphoreticular/hematopoietic cells
Reserve pool and storage space
Key symptom in spleen disease: Splenomegaly
Causes of splenomegaly:
1. Infections
Any infective agent that can cause blood-borne infection
2. Congestion (portal HTN)
3. Lympho-hematogenous disorders
Primary or secondary lymphomas
Splenic involvement by leukemias
Anemias
4. Immunologic-inflammatory conditions
Valvular (eg. infective endocarditis)
AMI
Arrhythmias
5. Storage disease
6. Others