JC49 (Medicine) - Lymphadenopathy and Lymphoma Flashcards
Ddx generalized lymphadenopathy
- Lymphoma: Low-grade cause wax-and-wane LN, High-grade cause rapidly growing masses
- Lymphoid Leukaemia, eg. CLL, ALL (less common in AML/CML)
- Infections: Viral, eg. IM, CMV, HIV, EBV Bacterial, eg. TB, brucellosis, syphilis, Typhoid fever Protozoal, eg. toxoplasmosis Fungal: Cryptococcus
- Connective tissue disease, eg. RA, SLE
- Infiltration, eg. sarcoidosis, amyloidosis
- Drugs, eg. phenytoin**, hydralazine
Ddx Localized lymphadenopathy
Localized lymphadenopathy
- Local infection
- Metastasis from solid tumors
- Lymphoma, esp Hodgkin’s lymphoma
Describe lymphadenopathy
- Sites
- Size cut-off
- Consistencies
- Fixation
- Overlying skin changes
Site:
- Localized in local infection and early lymphoma
- Generalized in late lymphoma
Size:
- Large (>1cm) usually abnormal
Consistency:
- Hard: carcinoma deposits
- Soft: may be normal
- Rubbery: may be due to lymphoma
Tenderness: indicates infection or acute inflammation
Fixation:
- Fixed: more likely to be infiltrated by carcinoma
Overlying skin:
- Inflammation indicates infection
- Tethering indicates carcinoma
List all lymph node groups and their drainage sites in body
Causes of submental and submandibular lymphadenopathy
Causes of Jugular, Posterior cervical and suboccipital lymphadenopathy
Causes of pre- and post-auricular Lymphadenopathy
Causes of supraclavicular and axillary lymphadenopathy
Causes of epitrochlear lymphadenopathy
Causes of Inguinal lymphadenopathy
History taking for lymphadenopathy
History:
LN itself: rapidly enlarging, tender (reactive) vs painless, rubbery/hard (malignant)
Localizing symptoms to suggest infection, malignancy
Constitutional symptoms, eg. fever, weight loss, night sweats
Relevant infective exposure, eg. cats, insect bite, travelling, venereal exposure, IVDU
Medications, eg. phenytoin
Physical exam for LN
Nature of LN: site, size (>1cm abnormal) consistency (hard vs rubbery vs soft), fixation (mobile vs fixed vs matted), tenderness (indicates rapid enlargement with capsule stretching)
Inspect and palpate drainage basin, eg. oral cavity, thyroid, parotid, external auditory meatus…
Other relevant signs, eg. hepatosplenoegaly, tonsils (also part of lymphoid system), abdominal mass, SVCO (if any)
Ddx lymphadenopathy based on consistency
Hard: solid malignancy, previous infl’n with fibrosis
Firm, rubbery: lymphoma, chronic leukaemia
Soft: acute leukemia, reactive
First-line investigations for lymphadenopathy
CBC/D, viral studies, serology
Imaging (CXR, USG, CT, MRI)
Biopsy:
- Fine-needle aspiration cytology (FNAC): cytological information only, useful in infection and solid organ malignancies (USELESS in lymphoma)
- Core-needle biopsy or incisional biopsy: provides histological information, useful for lymphoma
- Excisional biopsy: architectural details required for diagnosis of lymphoma
Ddx atypical lymphocytosis/ infectious mono- like syndrome
Viral infections: EBV, CMV, HIV, acute viral hepatitis
Bacterial: atypical organisms e.g. Mycoplasma pneumoniae, Legionella penumophila, Salmonella, Rickettsia
Mycobacterial: Disseminated TB
Dimorphic fungi: Talaromyces marneffei
Parasitic: Toxoplasma gondii
Drug reaction/ hypersensitivity
Acute lymphoblastic leukemia
Investigations for atypical lymphocytosis
PBS - atypical lymphocytes
Microbiology workup:
- Blood culture
- Sputum culture and AFB smear
Specific bacterial tests:
- Mycoplasma serology
- Urine for RAT against Legionella Antigen
- Widal’s test (salmonella)
Specific viral tests:
- CMV IgG and IgM and pp65
- Monospot test and EBV serology test (EBV DNA)
- HIV antibody test
Parasite:
- Toxoplasma serology test
Ddx mediastinal mass
- Lymph node enlargement: Lymphoma, Metastatic LN
- Thymoma
- Germ cell tumor
- Retrosternal goiter
- Dilated aortic arch (e.g. syphilis)
- Neurofibroma
Categorize Lymphomas
Describe the B-cell maturation process and lymphoid tissue involved
List Precursor B-cell neoplasms
B-lymphoblastic leukaemia
B-lymphoblastic lymphoma
List Pre-GC, GC and post-GC B-cell neoplasms
Describe the T-cell maturation process and lymphoid tissues involved
List T cell neoplasms
Precursor T cells:
T-lymphoblastic lymphoma/ leukaemia
Mature T cells:
Peripheral T-cell and NK-cell lymphomas/ leukaemia
Risk factors for lymphoma development **(Non-Hodgkin HL)
Viral infections:
- EBV: Hodgkin, DLBCL, Burkitt lymphoma
- HIV: HL, BCL
- HTLV-1: Adult T cell lymphoma/ leukaemia
- HCV: marginal zone B cell lymphoma
- HHV-8: primary effusion lymphoma (large BCL)
Bacterial infections: extra-nodal B cell lymphomas
- Helicobacter pylori - Gastric lymphoma (MALT)
- Chlamydia psittaci - Occular Adnexal Lymphoma
Immunocompromised states:
- Congenital immunodeficiency
- Acquired immunodeficiencies (e.g. HIV, drugs, organ transplant…etc)
- Autoimmune diseases: RA, SLE, Sjogren syndrome …etc
Environmental/ occupational:
- pesticides, hair dyes, dioxins
7 aims of investigations for lymphomas
- Accurate diagnosis
- Staging
- Detect complications of lymphoma
- Determine prognosis
- Determine suitability/ fitness for treatment
- Detect complication of treatment
- Assess response to treatment
Basic investigations and rationale for DIAGNOSIS of LYMPHOMA
CBC with diff.
LFT/ RFT (for AKI secondary to TLS, drug adjustment for CKD)
Serum electrolytes, LDH and urate (Risk of TLS, Proliferative index)
CXR (mediastinal involvement, risk of reactivation of chronic infections)
ESR (prognosis for Hodgkin’s)
B2- microglobulin (prognosis for Follicular lymphoma)
Serum protein electrophoresis (paraproteinaemia)
BM aspiration and trephine Bx (Staging)**
PET-CT with FDG (Staging)
Ddx precursor lymphoid cell neoplasm
Precursor B lymphoblastic leukaemia/lymphoma
Precursor T lymphoblastic leukaemia/lymphoma
Ddx mature B cell neoplasms
Pre-GC:
Mantle cell lymphoma (MCL)
GC: Follicular lymphoma (FL) Burkitt lymphoma (BL) Diffuse large B cell lymphoma (DLBCL) Nodular lymphocyte-predominant HL Classic Hodgkin lymphoma
Post-GC:
Chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL)
Marginal zone B cell lymphoma (MZL)
Lymphoplasmacytic lymphoma (Waldestrom macroglobulinaemia, WM, LPL)
Terminally differentiated:
Plasma cell neoplasms
Ddx mature T-cell lymphoma
Peripheral T cell lymphoma (PTCL) Anaplastic large cell lymphoma (ALCL) Adult T-cell lymphoma/leukaemia (ATL) T cell large granular lymphocyte leukaemia (LGL) T cell prolymphocytic leukaemia (T-PLL)
Ddx mature NK cell lymphomas
NK cell large granular lymphocyte leukaemia (LGL)
Aggressive NK cell leukaemia
Outline in detail: Staging system for lymphomas
Ann-Arbor Staging:
I:
Involvement of single LN region (eg. cervical, axillary, inguinal, mediastinal) or lymphoid structure (eg. spleen, thymus, Waldeyer’s ring).
II
Involvement of ≥2 LN regions or lymphoid structures on the same side of diaphragm.
III
Involvement of LN regions or lymphoid structures on both sides of diaphragm.
III.1 – involvement of spleen, splenic hilar, coeliac or portal nodes
III.2 – involvement of para-aortic, iliac, inguinal or mesenteric nodes
IV
Diffuse or disseminated involvement of ≥1 extralymphatic organs
Investigation and rationale for PRE-TREATMENT ASSESSMENT OF LYMPHOMA
- ECG and transthoracic echocardiogram: risk of cardiotoxicity with anthracyclines
- Lung function studies: risk of pulmonary fibrosis with bleomycin + Immune-mediated pneumonitis with Checkpoint inhibitors
- Hep. B and C serology: reactivation with immunosuppression
- HIV serology: HIV-AIDS close link with lymphoma
- G6PD assay: oxidative hemolysis with co-trimoxazole/ recombinant urate oxidase - Rasburicase
Hodgkin’s lymphoma
- Demographics
- S/S
- Subtypes
- Which subtype has young age of presentation?
- Bi-modal age distribution: Late adolescence/young adulthood + old age, M>F
- S/S:
Painless lymphadenopathy at neck and chest, fluctuates in size with URTI symptoms
Incidental mediastinal mass or compressive SOB, cough, chest apin
Moderate splenomegaly +/- hepatomegaly
Late skin involvement
Fever, drenching night sweats, general pruritis
Subtypes:
1. Classical HL:
- Nodular sclerosis* - classical Reed-Sternberg cells with Eosinophilia
- Lymphocyte rich
- Lymphocyte depleted
- Mixed cellularity
2. Nodular lymphocyte-predominant type: No Reed-Sternberg cells, tumor B cell predominant
*Nodular Sclerosis Classical HL has young age of presentation (15-35)
Hodgkin lymphoma
Treatment
ABVD = doxorubicin (Adriamycin), bleomycin, vinblastine, dacarbazine
± Radiotherapy
Salvage combination chemo (eg. ICE, GVD) followed by autologous HSCT
Diffuse Large B-cell lymphoma
- Define classification
- Most associated disease
- Gene mutation
- S/S
- Treatment
- Most common Non-Hodgkin Lymphoma
- AIDS-DEFINING MALIGNANCY
- CREBBP* mutation (chromatin remodeling), EZH2 and MYC
S/S: Defined to organs: e.g. Primary CNS or Primary Mediastinal DLBCL
- Rapidly enlarging mass: most commonly neck/abdominal
- Late extranodal involvement:
GI - anorexia, pain, fullness, GIB;
CNS: headache, focal neurological, seizures…etc
- B sypmtoms: Fever, night sweats, Weight loss
- Bone marrow involvement (rare)
- Compressive symptoms: SVCO, cord compression, airway
Treatment:
R-CHOP, EPOCH-R for double hit DLBCL
Auto-HSCT for chemosensitive relapse,
CAR T-cell therapy for CD19+ DLBCL
Burkitt lymphoma
Genetic cause
S/S
Treatment
Genetics:
Deregulated expression of cMYV due to reciprocal translocation with Ig heavy chain t(8;14), or variant light chain gene loci t(2;8) or t(8;22)
S/S:
- Large abdominal mass
- B-symptoms: fever, night sweats, weight loss
- Extra-nodal involvement with BM infiltration
- Leptomeningeal involvement
Treatment:
Rituximab + combination chemotherapy
TLS
Follicular lymphoma
Genetic cause
S/S
Treatment
Low-growing or indolent form of non- Hodgkin lymphoma (NHL)
Genetics:
t(14;18), CREBBP, MLL2 mutations (chromatin remodeling)
S/S: non-specific, late advanced presentation
- Lymphadenopathy
- B symptoms: fever, night sweat, weight loss
Treatment:
Anti-CD20 mAb + Purine analogue/ alkylating agent chemotherapy
Marginal zone B-cell lymphoma
- Cause
- Classification
- Associated infections/ condition
- Treatment
Caused by chronic antigenic stimulation by microbial pathogens or autoantigens/ Autoimmune disease
Extranodal MZL or Mucosa-Associated Lymphoid Tissue (MALT)most common
- Gastric MALT (H.pylori)
- Cutaneous MALT (B. burgdorferi or B afzeli)
- Ocular adnexal MALT (C. psittaci)
- Pulmoanry or parotid MALT (Sjogren syndrome)
- Thyroid MALT (Hasimoto thyroiditis)
Nodal MZL (Hepatitis C)
Splenic MCL/ SMZL (hepatitis C)
Treatment:
Gastic MALT: triple therapy for H. pylori, Radiation, Anti- CD20 mAb
Non-gastric MALT: Radiation, doxycycline, Anti-CD20 mAb, Bedndamustine +/- R-CHOP
Nodal MZL: Radiation, chemo, immunotherapy
Splenic MZL: Ibrutinib, Lenalidomide, Anti-CD20 mAb
Lymphoplasmacytic lymphoma
- Cell origin
- Types
- S/S
- Defining feature
- Treatment
Lymphoplasmacytic lymphoma
- Waldestrom macroglobulinaemia or LPL
- Post-germinal centre IgM memory B cell before isotype class switching, MYD88 mutation***
- IgM monoclonal gammopathy ***
S/S:
Hyperviscosity syndrome Peripheral neuropathy Cryoglobulinaemia BM infiltration: anaemia and bleeding tendency Lymphadenopathy Hepatosplenomegaly
Treatment:
- Emergency plasmapheresis for hyperviscosity syndrome
- Rituximab + chemotherapy
Mantle cell lymphoma
Demographic
Cell of origin
Genetic Cause
S/S
Mid-60s, male-predominant
Subtype of NHL
t(11; 14), ATM, TP53 and chromatin modification mutations, alter cyclin D1
naïve, pre-germinal centre B lymphocytes
S/S
- Special invasion of GIT - Lymphomatous polyposis of large bowel
- Extra-nodal involvement: BM infiltration
- Lymphadenopathy
- B symptoms
CLL/SLL
Chronic lymphocytic leukaemia/ Small lymphocytic lymphoma
- Demographics
- S/S
- Staging system
Most prevalent lymphoid neoplasm in North America and Europe
Median age 72, M:F = 2:1
S/S: Largely asymptomatic, incidental find Leukocytosis/ lymphocytosis Lymphadenopathy Splenomegaly Anemic and thrombocytopenia S/S
Staging:
Binet staging/ Rai staging
Extra-nodal NK/ T-cell lymphoma
- Demographic
- Risk factors
- Cells of origin
- S/S
- Treatment
Demographic:
Asian, with EBV infection
Exposure to pesticides and chemical solvents
NK- or γδ T-cell
CD2, cytoplasmic CD3 (CD3ε), CD45, NK-cell marker CD56
S/S: Nasal, Palatal ulcer or perforation Nasal obstruction Bloody rhinorrhea swelling of cheek or orbit, sore throat, and hoarseness Fever and night sweats
Tx:
SMILE: dexamethasone, methotrexate, ifosfamide, L-asparaginase and etoposide
Spectrum of treatments for lymphomas (list general classes of drugs/ treatment)
Pharmacological options: Multi-agent chemotherapy +/- monoclonal antibodies
- Targeted therapy: BTK/ BCL-2 inhibitors
- Immuno-conjugates
- Checkpoint inhibitors
- Chimeric antigen receptor T cell therapy
Transplant:
- Autologous HSCT
Supportive:
- Prevention of TLS (e.g. recombinant urate oxidase)
- Management of disease/ Tx complications
