1. Approach to Lymphadenopathy
PROF:AKMAL JAMAL
FCPS;FRCSEd:
2013

2. Case
41 yo male school teacher presents to your office with right sided cervical lymphadenopathy. His past medical history is significant for hypertension and dyslipidemia. He noticed the lump in his neck last week. He has not experienced any fevers, chills or weight loss. He denies any sore throat, ear pain or dental problems. His vital signs are stable. On physical exam he has a 2cm anterior cervical lymph node which is firm, non-tender and mobile. His HEENT exam is unremarkable. No skin lesions are evident. No other lymphadenopathy is found. How should you proceed with this patient?
Location and duration typical for viral etiology. Have your patient follow up for annual physical next year.
Proceed to fine needle aspiration.
Check a CXR and cbc.
Have patient follow up in 3-4 weeks.

3. Learning Objectives
Provide an approach to the patient with peripheral lymphadenopathy
Be able to differentiate between benign and serious illness
Knowledgeable of nodal distribution and anatomic drainage
Present a substantial differential diagnosis
Indications for nodal biopsy

4. Objectives Approach to Adenopathy Who to investigate
When to investigate
How to define risk for underlying malignancy

5. Definition: Lymphadenopathy
Lymph nodes that are abnormal in
size
consistency or
number
characterized

6. Definitions Pathologic Lymph Node Acute Lymphadenopathy
>2cm in children is considered abnormal
Acute Lymphadenopathy
< 2 weeks duration
Subacute Lymphadenopathy
2-6 weeks duration
Chronic Lymphadenopathy
> 6 weeks duration

7. Classification: Lymphadenopathy
Generalized- if lymph nodes are enlarged in two or more noncontiguous areas
Localized- if only one area is involved.
characterized

8. Distinguishing between two is important in formulating a differential diagnosis.
3/4 of patients will present with localized lymphadenopathy
1/4 with generalized lymphadenopathy.

9. Why do lymph nodes enlarge?
Increase in the number of benign lymphocytes and macrophages in response to antigens
Infiltration of inflammatory cells in infection (lymphadenitis)
In situ proliferation of malignant lymphocytes or macrophages
Infiltration by metastatic malignant cells
Infiltration of lymph nodes by metabolite laden macrophages (lipid storage diseases)

10. Normally palpable lymph nodes in healthy people?
The Lymphatic System
Normally palpable lymph nodes in healthy people?

11. submandibular, axillary inguinal The Lymphatic System
Normally palpable lymph nodes in healthy people.
submandibular,
axillary
inguinal

12. Lymphatic System

13. Lymphatic System
Network that filters antigens from the interstitial fluid
Primary site of immune response from tissue antigens
Lymphatic drainage in all organs of the body except brain, eyes, marrow and cartilage
Flaccid thin walled channelsprogressive caliber
600 lymph nodes in body
Slow flow, low pressure system returns interstitial fluid to the blood system
Primary site of immune response from tissue antigens

14. Lymph nodes Capsular shell Fibroblasts and reticulin fibers
Macrophages
Dendritic cells
T cells
B cells
Immune response: flow of blood and lymph can increase as much as 25X can swell up to 15X normal size
Invasion by malignant cells or propagation of an inflammatory process

16. anatomy
Each lymph node is a bean shaped organ, with an outer connective issue frame work, which dips into the structure forming numerous septa.
Node has an outer convex surface and an inner concave surface- the Hilum
Afferent vessels enter.
Efferent vessels exit
Blood vessels

17. HISTOLOGY CORTEX: MEDULLA: TWO ZONES: A darkly staining cortex
And a lightly staining medulla
CORTEX:
Several rounded areas { lymphatic follicles}
Paler germinal center which contain actively dividing B-lymphocytes.
The para-follicular area contains T-lymphocytes
MEDULLA:
Lymphocytes arranged less densely in the form of cords along the reticular network
Sinusoids are present for free flow of lymph

18. Lymph passing through these sinuses comes in intimate contact with macrophages & lymphocytes present in the node.
Bacteria and other particulate matter present in the lymph are filtered by these cells

19. function
They are centers of lymphocyte production. Both B-lymphocytes and T-lymphocytes are produced here by multiplication of pre-existing lymphocytes.
Filter the products from lymph such as bacteria and other particulate matter and to prevent their entry into systemic circulation.
The antibodies produced by the B-Lymphocytes are carried to the circulation… and indirectly help in mounting an immune response.

20. Peripheral lymphadenopathy
Most cases benign, self limited illness
Primary or secondary manifestation of 100 illnesses
The CHALLENGE is to decide if it is representative of a serious illness…
Invasion by malignant cells or propagation of a inflammatory process

21. Parameters to help distinguish between benign and serious illness
Age
Character
Location

22. “Malignancy much more common in patients greater 50 yrs of age”
Not exactly

23. Algorithm to evaluate Lymphadenopathy
History
Physical exam
Confirmatory testing
Indication for biopsy

24. History Localizing symptoms or signs to suggest a specific site
Constitutional symptoms: B symptoms
(fever, night sweats, >10%body wt >6months)
Epidemiologic clues: occupation, travel, high risk behavior
Medications

25. Medications That May Cause Lymphadenopathy
Allopurinol Atenolol (Tenormin) Captopril (Capozide) Carbamazepine Cephalosporins Gold Hydralazine
Penicillin Phenytoin Primidone Pyrimethamine Quinidine Sulfonamides Sulindac

26. Physical Examination

27. Lymph node character Size Site Consistency Pain with palpation
Picture of lymph node sites

28. Size Greater than one centimeter generally considered abnormal
Exception inguinal area, lymph nodes commonly palpated (>1.5 cm)
Size does not indicate a specific disease process
Obese and thin population

29. Pain…..
Indication of rapid increase in size: stretch of capsular shell
NOT useful in determining benign vs malignant state
Inflammation, suppuration, hemorrhage

30. Consistency Stone hard: typical of cancer usually metastatic
Firm rubbery: can suggest lymphoma
Soft: infection or inflammation
Shotty “buckshot under skin”
Suppurated nodes: fluctuant
Matted

31. Location, location, location

32. Post cervical: scalp, neck skin of arms thorax cervical and axillary nodes (lymphoma, head/neck ca)

33. Facial Papule with Adenopathy

37. Suppurative Lymphadenitis with Overlying cellulitis

38. Mycobacterial Lymphadenitis

39. Mycobacterial Lymphadenitis

41. Famous nodes Virchows Left supraclavicular (abdominal or thoracic ca)
Sister Joseph
Para-umbilical (gastric adenoca)
Delphian node
Prelaryngeal (thyroid or laryngeal ca)
Node of Cloquet (Rosenmuller node)
Deep inguinal near femoral canal
Surgeon William J Mayo’s Scrub nurse predict the findings when scrubbing abdomen preoperatively

42. Creating a Differential
CHICAGO

43. Causes
It results from a vast array of disease processes whose broad categories are easily recalled using the mnemonic “MIAMI” representing
Malignancies,
Infections,
Autoimmune disorders,
Miscellaneous and unusual conditions, and
Iatrogenic causes.

44. Chicago Cancer
Heme malignancies: Hodgkins, NHL, acute and chronic leukemias, waldenstroms, multiple myeloma (plastmocytomas)
Metastatic: solid tumor breast, lung, renal, cell ovarian

45. cHicago Hypersensitivity syndromes
Serum sickness
Serum sickness like illness
Drugs
Silicone
Vaccination
Graft vs Host
Serum sickness TYPE III immune complex mediated antibody antigen and complement cascade (horse serum to treat diptheria) humoral response to foreign protein

46. Specific Medications Cephalosporins Atenolol Captopril Dilantin
Sulfonamides
Carbamazepine
Primodine
Gold
Allupurinol
Believed to be caused by a different mechanism which is NOT classical serum sickness…delayed reaction to above

47. Chicago Infections Viral Bacterial Protozoan Mycotic
Rickettsial (typhus)
Helminthic (filariasis)

48. VIRAL EBV…mono spot test
CMV….cmv titers, immunsuppresed, transplant recipient, recent blood transfusion
HIV…IV drug use, high risk sexual behavior
Hepatitis….IV drug use
Herpes Zoster….superficial cutaneous nodules

49. Bacterial Staph/strep: cutaneous source, lymphadenitis
Cat scratch: bartonella hensalae, two weeks after inoculation
Mycobacterium: TB and non-tb, host characteristics (HIV, foreign born, low socioeconomic status, homeless)
Cat scratch (bite, scratch or flea bite): two weeks after inoculation
Half of tb (Mexico, Philippines, Vietnam, India, china)

50. Lt cat scratch
Rt lympahdenitis with suppuration

51. Spirochete
Syphilis: Treponema pallidum Primary localized inguinal lymph nodes and secondary, non-treponemal, treponemal
Lyme disease

52. Protozoan
Toxoplasmosis: ELISA assay, intracellular protozoan toxoplasmosis gondii….bilateral, symmetrical, non-tender cervical adenopathy
…consider undercooked meat, reactivation in immuncompromised host
Felines protozoan completes reproductive cycle: oocytes in feces, ingested by humans other animals : predominately undercooked meat, invade gi epithelium and lie dormant in neural and muscular tissue, 10% adults are seropositive

53. chicago Connective Tissue Disease
Rheumatoid Arthritis
SLE
Dermatomyositis
Mixed connective tissue disease
Sjogren
Arthralgias, skin manifestations

54. chicago Atypical lymphoproliferative disorders
Castleman’s disease
Wegeners
Angioimmuonplastic lymphadenopathy with dysproteinemia
Lymphoprolifertative disorder (associatin with HIV and HHV-8) localized no systemic symptoms and systemic fevers night sweats Multicentric form

55. chicaGo Granulomatous
Histoplasmosis
Mycobacterial infections
Cryptococcus
Silicosis: coal, foundry, ceramics, glass
Berylliosis: metal, alloys
Cat Scratch

56. OTHER…….chicago RARE Kikuchi Rosia Dorfman Kawasaki
Transformation of germinal centers
Young woman painless lymphadenopathy unilateral in cervical region resolves in 3 months unknown etiology: histiocytic necrotiziing lympadenitis
RD: greatly exaggerated lymph node reaction children bl cervical lymph node

57. Non-Infectious Lymphadenopathy

58. Kawasaki Disease Lymphomucocutaneous Disease
Five Characteristics of Disease (4/5 for diagnosis)
Fever >5 days
Cervical lymphadenopathy (usually unilateral)
Erythema and edema of palms and soles with desquamation of skin
Nonpurulent Bilateral Conjunctivitis
Strawberry Tongue
Treatment
IVIG and Aspirin

59. Systemic Manifestations of Kawasaki Disease

60. Kikuchi-Fujimoto disease
Also known as necrotizing lymphadenitis
Benign condition
Affects young Japanese girls
Associated Signs and Symptoms
Fever
Nausea
Weight loss
Night Sweats
Arthralgias
Hepatosplenomegaly
Thought to have viral or autoimmune etiology
The majority spontaneously regress within 6 months, however some patients have recurrences

61. Rosai-Dorfman Massive, painless, bilateral cervical adenopathy
Benign condition
Generalized proliferation of sinusoidal histiocytes
First decade of life with 2M:1F
Associated signs and symptoms
Fever
Neutrophilic leukocytosis
Polyclonal hypergammaglobulinemia
Most patients will get a biopsy given the large adenopathy
Characteristic biopsy showing sinus expansion with histiocytes and phagocytosed lymphocytes (Foucar 1990)
Treatment is supportive and most patients have spontaneous regression

62. Rosai-Dorfman Lymphadenopathy

63. Langerhans Cell Histiocytosis
Eosinophilic Granuloma
Solitary bone, skin, lung, or stomach lesions
Hands-Schuller-Christian Disease
Diabetes Insipidus, Exophthalmos, Lytic bone lesions
Letterer-Siwe disease
Life threatening multisystem disorder
50% 5 year survival
1/3 of patients will have background LAD
Histopathology shows normal lymph node architecture but increase sinusoidal Langerhans’ cells, macrophages, and eosinophils
Treatment with topical steroids, oral steroids, and even chemoradiation therapy

64. Investigations
Unexplained lymphadenopathy without signs or symptoms of serious disease or malignancy can be observed for one month, after which specific imaging or biopsy should be performed
fine-needle aspiration, excisional biopsy remains the initial diagnostic procedure of choice.
Modern cross-sectional imaging modalities such as ultrasound
(US), computed tomography (CT) and magnetic resonance (MR)
imaging allow reliable detection of cervical lymph nodes. However,
the differentiation between benign and malignant lymph
nodes remains challenging
Alternative imaging modalities such as single photon
emission computed tomography (SPECT) and positron emission
tomography (PET) can help to differentiate between benign and
malignant lymph nodes

65. Wait 3-4 weeks and reexamine
No indication for empiric antibiotics or steroids
Glucorticoids can be harmful and delay diagnosis can obscure diagnosis due to lympholytic affect

66. Unexplained Generalized lymphadenopathy
Always requires an evaluation
Start with CXR and CBC
Review Medications
PPD, RPR, Hepatitis screen, ANA, HIV
No yield on above test: Biopsy most abnormal node

67. Role of Ultrasound No radiation exposure
Good for following the progress of an abscess
Differentiate Reactive vs Malignant nodes
Reactive
<1 cm
Oval (S/L ratio <0.5cm)
Normal hilar vascularity
Low resistive index with high blood flow
Malignant
>1 cm
Round (S/L ratio >0.5cm)
No echogenic hilus
Cogaulative necrosis present
High resistive index with low blood flow
Extracapsular spread
Sensitivity 95% and Specificity 83% for differentiating reactive vs metastatic lymph nodes

68. The Role of FNA Minimally invasive Low morbidity
Not as reliable in children as in adults so you can only trust FNA if it is positive (Twist 2000)
Chau et al. 2003
Evaluated FNA of 289/550 patients referred with LAD
Sensitivity 49% and Specificity of 97%
False negative rate of 45%
83% of false negatives were lymphomas

69. The Role of Excisional Biopsy
Still the gold standard for diagnosis
Consider if FNA is inconclusive or if FNA is negative but your suspicion for malignancy is high
You must excise the largest and firmest node that is palpable and must remove the node with the capsule intact (Twist 2000)

70. BIOPSY
Can be done by bedside, open surgery, mediastinocopy or by needle aspiration*
FNA not recommended cannot distinguish between lymphomas (nodal architecture needs to be intact)
FNA reserved for established diagnosis and to demonstrate recurrence

71. Diagnostic Yield
Ideally axillary and inguinal nodes are avoided as often demonstrate reactive hyperplasia
Preferred supraclavicular, cervical, axillary, epitrochlear, inguinal
Complications include vascular and nerve injury

72. Unexplained Lymphadenopathy
Localized Lymphadenopathy
When to biopsy ?

73. Unexplained Lymphadenopathy
Localized Lymphadenopathy
Patients with
benign clinical history,
an unremarkable physical examination
no constitutional symptoms
should be reexamined in three to four weeks to see if the lymph nodes have regressed or disappeared.

74. Unexplained Lymphadenopathy
Localized Lymphadenopathy
Patients with unexplained localized lymphadenopathy who have
constitutional symptoms or signs,
risk factors for malignancy or
lymphadenopathy that persists for three to four weeks should undergo a biopsy.

75. Fine Needle Aspirate
Convenient, less invasive, quicker turn-around time
Most patients with a benign diagnosis on FNA biopsy do not undergo a surgical biopsy

76. Case
41 yo male school teacher presents to your office with right sided cervical lymphadenopathy. His past medical history is significant for hypertension and dyslipidemia. His medications include hctz and simvastatin. He has no known drug allergies. He believes he noticed the lump in his neck last week. He has not experienced any fevers, chills or weight loss. He denies a sore throat, ear pain or dental problems. His vital signs are stable. On physical exam he has a 2cm anterior cervical lymph node which is firm, non-tender and mobile. His HEENT exam is unremarkable. No skin lesions are evident. No other lymphadenopathy is found. How should you proceed with this patient?
Location and duration typical for viral etiology. Have your patient follow up for annual physical next year.
Proceed to fine needle aspiration
Check a CXR and cbc
Have patient follow up in 3-4 weeks.