1. Cancer Education Day May 13, 2016

2. Approach to Adenopathy and Splenomegaly Disclosures – None

3. Case 52 year anxious old female presents with 2 week history of cervical chain lymph node; otherwise well. Feels somewhat rubbery, no other significant lymph nodes. She has been feeling well otherwise. Best investigation: – FNA – Excisional biopsy – Return to clinic in 2 weeks – CXR and CBC

4. Learning Objectives Know when to biopsy lymph node in a presenting patient Know the work up of a patient with concerning lymph nodes Know the benign causes of generalized adenopathy Know the advantages and disadvantages of different biopsy techniques

5. Normal function of the lymph node: To allow interaction between components of the immune system and sensitize the immune response. This response normally subsides in < 4 weeks. ~ 600 LN n our bodies

6. Peripheral adenopathy Most are benign, self limited illness Primary/ secondary manifestations of 100 illnesses The CHALLENGE is to decide if it is representative of a serious illness

7. Epidemiology Lee et al 1980 – Referral centres 925 had biopsies of LN Age% benign%lymphoma% carcinoma < 3079%6% > 5016% 44%

8. Dutch study Fijten 1988 0.6 annual incidence of generalized adenopathy 2,556 present with unexplained lymphadenopathy 10% referred to subspecialist – 3.2% required biopsy 1.1% had malignancy > 40 years of age – 4% risk of cancer vs. 0.4% in patients younger than age 40

9. Size/ symptoms > 1 cm considered abnormal – UNLESS in groin area where LN are commonly palpated; 1.5 cm – 2.0 cm can be normal LN more easily palpated in thin patients Pain does not give any direction wrt etiology – May be primarily or secondarily infected/ inflamed

10. Consistency Stone hard – carcinoma Rubbery – lymphoma Soft – infection

11. Location Rubella conjunctiva/ eyelid infections

12. Location Rubella conjunctiva/ eyelid infections Bilateral cervical: Dental infections, TB, mono, cocidiodomycosis, sarcoid, lymphoma, leukemia Unilateral: naspharyngeal carcinoma

13. Location Rubella conjunctiva/ eyelid infections Bilateral cervical: Dental infections, TB, mono, cocidiodomycosis, sarcoid, lymphoma, leukemia Unilateral: nasopharyngeal carcinoma consistency

14. Location Supraclavicular: almost always abnormal when isolated : usually cancer in chest or abdomen Right – lung / mediastinum Left – Virchow’s node: stomach/ ovaries/ testes/kidney

15. Location : Axillary Isolated Axillary: Infection/ breast cancer

16. Location Inguinal – Isolated : infection – Generalized: lymphoma/ leukemia

17. Causes of adenopathy Infections – Localized: eg strep pharyngitis – TB, syphilis, mono, hepatitis, toxoplasmosis, fungal infection Cancers – lymphomas,leukemias Immunological Conditions – Drug reactions/ serum sickness – Sarcoid – Connective tissue disease ; RA, SLE – Chronic dermatological disorders ( eg. eczema) Rare disorders: – Castelman’s/ Wegeners; Dermatomyositis; Rosai Dorfman; Kawasaki; Graves and Addison’s, Lipid Storage disease

18. Clinical History Age – children react much more dramatically to weak antigens ( viruses) than adults Drugs, allergies, animal exposures, hobbies and occupations, HIV risk factors Tender, painful, rapid onset – more likely inflammatory / infectious B symptoms, pruritis – cancer / TB/ hepatitis

19. Work up : Lab for Chronic adenopathy > 3 weeks CBC and diff with peripheral smear LDH, uric acid B henselae (catscratch) if exposed to a cat TB skin test LFT/ BUN/ Creatinine Consider titres for EBV, CMV, toxo, HIV If autoimmune considered: RF, ANA If sarcoid considered: ACE level

20. CXR If supraclav: CT chest, abdomen, pelvis Work up : Imaging for Chronic adenopathy > 3 weeks

21. Biopsy : when and how If infectious etiology is considered – antibiotics and re-evaluate in 2 – 4 weeks If more suspicious of malignancy – biopsy – FNA – Core – Excisional – EBUS/ Trans bronchial needle aspiration

22. Types of biopsies Type of biopsyAdvantagesLimitations Fine Needle Aspiration (FNA) Easy to obtain with ultrasound/ CT guidance of peripheral adenopathy : Can identify carcinoma. Would likely not identify lymphoma/ leukemia. If can get enough for flow cytometry would help in diagnosis. Only a few cells. Can identify infectious cause eg. TB. Can identify renal cell carcinoma, Willms tumor. Will not diagnose Hodgkin’s nor T cell lymphoma Core BiopsyMore tissue – more confident diagnosis. Able to send flow cytometry to confirm lymphoma diagnosis. Usually able to obtain 4 – 6 biopsies. Will not identify Hodgkin’s lymphoma.

23. Types of biopsies Core biopsy

24. Types of biopsies Type of biopsyAdvantagesLimitations Fine Needle Aspiration (FNA) Easy to obtain with ultrasound/ CT guidance of peripheral adenopathy : Can identify carcinoma. Would likely not identify lymphoma/ leukemia. Only a few cells. Can identify infectious cause eg. TB. Can identify renal cell carcinoma, Willms tumor. Core BiopsyMore tissue – more confident diagnosis. Able to send flow cytometry to confirm lymphoma diagnosis. Usually able to obtain 4 – 6 biopsies. Will not identify Hodgkin’s lymphoma. Excisional BiopsyMost tissue. Necessary for the diagnosis of Hodgkin’s ( only need core biopsy for RELAPSED Hodgkin’s) Most invasive. Takes extra time to arrange.

25. Hodgkin’s lymphoma Lymph Node CD 15/ 30 Stains positive

26. Types of biopsies Type of biopsyAdvantagesLimitations Fine Needle Aspiration (FNA) Easy to obtain with ultrasound/ CT guidance of peripheral adenopathy : Can identify carcinoma. Only a few cells. Can identify infectious cause eg. TB. Can identify renal cell carcinoma, Willms tumor. Would likely not identify lymphoma/ leukemia. Core BiopsyMore tissue – more confident diagnosis. Able to send flow cytometry to confirm lymphoma diagnosis. Usually able to obtain 4 – 6 biopsies. Will not identify Hodgkin’s lymphoma. Excisional BiopsyMost tissue. Necessary for the diagnosis of Hodgkin’s ( only need core biopsy for RELAPSED Hodgkin’s) Most invasive. Takes extra time to arrange. EBUS/ TBNANecessary for lung lesions that cannot be reached in any other way Same as FNA

27. Generalized adenopathy H & P for infectious etiology Monospot/ VDRL/ HIV/ ANA/ RF

28. EBUS

29. Case 52 year anxious old female presents with 2 week history of 2 cm cervical chain lymph node; otherwise well. Feels somewhat rubbery, no other significant lymph nodes. She has been feeling well otherwise. No history of connective tissue disease, chronic skin disorders nor infection. Best investigation: 1.FNA 2.Excisional biopsy 3.Return to clinic in 2 weeks 4.CXR and CBC

30. Case 52 year anxious old female presents with 2 week history of 2 cm cervical chain lymph node; otherwise well. Feels somewhat rubbery, no other significant lymph nodes. She has been feeling well otherwise. No history of connective tissue disease, chronic skin disorders nor infection. Best investigation: 1.FNA 2.Excisional biopsy 3.Return to clinic in 2 weeks 4.CXR and CBC

31. Case #2 45 year old man with palpable spleen on exam. Asymptomatic. No adenopathy. CBC shows no cytopenias. No “cytoses”. What is the next steps in management? 1.Biopsy spleen 2.Bone marrow biopsy 3.Ultrasound abdomen 4.Liver function tests and liver biopsy

32. Approach to splenomegaly What is an enlarged spleen? – 16% of palpable spleens are normal on imaging – Upper limit normal on imaging = 11 to 14 cm on US – CT normal upper limit of splenic length is 13 cm – Subjective on the part of the radiologist – May be normal in some young men * * Hesdorffer CS True Idiopathic splenomegaly Scand J Haematol 1986

33. Causes of splenomegaly Varies by country 11 – 45% of massive splenomegaly in Africa is due to Tropical Splenomegaly Syndrome of malarial origin Up to 30% from schistosomiasis

35. Clinical Assessment Early satiety Cytopenias B symptoms ( fever, drenching night sweats, weight loss ) and adenopathy suggest hematological, infectious or inflammatory cause Family history (may be none with Gaucher’s disease – autosomal recessive)

36. Liver disease: Alcohol intake Infectious disease: travel, sexual contacts, IV drug use, exposure to animals, predisposition to infective endocarditis

37. Physical Exam Splenomegaly, adenopathy, signs of endocarditis ( may have murmur) Findings will not be specific to the underlying diagnosis

38. Recommended Investigations for all 1.Hematology : CBC and diff, peripheral smear, ESR, INR, PTT 2.Biochemistry : BUN, creatinine, electrolytes, LFTs, C reactive protein, LDH, B 12 and RBC folate 3.Microbiology : monospot, Hepatitis screen 4.Immunology : ANA, RF 5.Imaging : US or CT abdomen, CXR 6.Urine: U/A for protein, blood

39. Consider extra investigations 1.Hematology: direct Coombs, Retic count, Malaria smear, Hgb electrophoresis 2.Biochemistry: Serum ACE, SPEP, Serum free light chains 3.Microbiology: blood cultures, sputum for C & S and gram stain, Mantoux TB skin test, serology for HIV, CMV, toxo, brucella 4.Imaging: US with duplex doppler, CT Chest, Abdo, Pelvis; TEE

40. How to narrow the differential diagnosis Infectious causes associated with fever Hepatic disease with abnormal LFT, hepatomegaly, low platelets, leucopenia 84% of progressive splenomegaly are associated with hematological diseases – Usually associated with “cytoses” – erythro/leuco/thrombo; left shift of neutrophils (MPN)

41. Imaging Usually diffusely enlarged Focal lesions: – Malignant: carcinoma, lymphoma – Infective: abscess, TB, histoplasmosis, fungal, – Vascular: hematoma, angioma – Granulomatous: sarcoid – Cysts

42. Second Line Investigations If underlying etiology has not been identified by work up so far Bone marrow biopsy and aspirate, unless young and asymptomatic Liver biopsy if LFT abnormal or hepatic lesions Screen for Gaucher’s disease

43. Gaucher’s disease

44. Wilson’s Disease and Cirrhosis

45. NHL

46. Splenic infarct LUQ pain Common complication of splenomegaly; no medical concerns, pain control

47. Myeloproliferative Neoplasms : CML, Polycythemia Vera, Myelofibrosis

48. Next steps to discover etiology 1.Watchful waiting 2.Splenic biopsy 3.Diagnostic splenectomy

49. Watch and Wait Young asymptomatic people with recent infection, may even have mild cytopenias Even if patients have indolent lymphoma, watch and wait is appropriate, as treatment is not indicated Patient should not have ongoing fever, night sweats nor weight loss

50. Splenic biopsy Most useful in focal lesions to rule out malignancy FNA : 84% accuracy in diagnosing NHL Core: – increased risk bleeding – 10%, reports of needing splenectomy in earlier studies ( now using smaller needles) – Allow diagnosis up to 90% of cases – Usually only used for focal lesions

51. When to do a splenectomy

52. Diagnostic Splenectomy It is worth considering if the the splenectomy will bring other benefits besides the diagnosis : reversal of cytopenias, relief of pain Performed with decreasing frequency today Can still get diagnosis with laparoscopic It is the treatment of choice in primary splenic marginal zone lymphoma Would expect no increase in morbidity or mortality with vaccinations pre-op – Recent study showed no complications with 434 years of patient followup after splenectomy for ITP* *Schwartz et al J Hematol 2003: 94 Pozo et al Splenomegaly Blood Reviews 2009; 105

53. Case #2 45 year old man with palpable spleen on exam. Asymptomatic. No adenopathy. CBC shows no cytopenias. No “cytoses”. What is the next steps in management? 1.Biopsy spleen 2.Bone marrow biopsy 3.Ultrasound abdomen 4.Liver function tests and liver biopsy

54. Case #2 45 year old man with palpable spleen on exam. Asymptomatic. No adenopathy. CBC shows no cytopenias. No “cytoses”. What is the next steps in management? 1.Biopsy spleen 2.Bone marrow biopsy 3.Ultrasound abdomen 4.Liver function tests and liver biopsy

55. QUESTIONS?