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1 Enterprise Interest Nothing to declare

2 CASE -2 1 Andleeb Abrari MD, DNB, FRCPath 1 Urmi Mukherjee MD 1 Nayana Patil DCP 2 Rahul Naithani MD 3 Nevin Kishore MD, FRCP 4 Anil K. Anand MD 5 Harit K. Chaturvedi, MS, MCh Author affiliations : Departments of 1 Histopathology; 2 Medical oncology; 3 Pulmonolgy and Respiratory Medicine; 4 Radiation Oncology; 5 Surgical Oncology - Max Healthcare Institute Limited, New Delhi, India Conflicts of interest - None

3 The patient - 55 year old male with intermittent cough of 6 month duration Also: breathlessness on walking weight loss of 4 kilograms in one month blood flecked sputum for a fortnight

4 Imaging: Chest X-ray right hilar, rounded soft tissue mass -? lymph node,? aortic root aneurysm CT chest - well defined heterogeneous enhancing lesion, anterior mediastinum in the right pulmonary hilum with imaging possibility of thymic lesion or lymphoma being raised 4

5 EBUS - intrabronchial irregular excrescence at the entry of anterior segment of right upper lobe bronchus TBNA - cytology material was low yield - (few lymphomononuclears, with histiocytic giant cells Cell block- hypocelluar, with nondescript stromal elements and sparse mononuclear inflammatory cells 5

6 A EBUS- TBNA material 6

7 Cell Block Section 7

8 EBB - mucosal bits, with amorphic eosinophilic material histiocytic giant cell reaction modest population of interspersed plasma cells Tinctorial weak congophilia and putative birefringence + 8

9 Endobronchial Biopsy 9

10 Congo Red 10

11 CD 138 ; CD38 11

12 Light Chain IHC. Kappa (left); Lambda (right) 12

13 EBB - AL amyloidoma with possibility of associated plasma cell dyscrasia - on histopathology report With recommendations 13

14 SPEP - negative for monoclonal band IFE Normal pattern Autoimmune work-up Negative Haematologic parameters WNL Bone marrow aspirate / biopsy - negative for neoplastic systemic plasma cell disease KFT, KFT WNL 14

15 FDG PET FDG avid (SUV max 9.9) heterogeneously enhancing, mass lesion 9.4 x 7.0 x 7.1 cm in the right hilar and suprahilar region Encasement of subsegmental branches of right upper and middle lobe bronchi Abutting right pulmonary artery, right superior pulmonary vein and compressing the SVC No other significant FDG avid lesion was detected 15

16 FDG-PET Images 16

17 With this context, after MDT approval the patient underwent excision of the right hilar mass Piecemeal, very firm to hard brown tissue bits, measuring 10 x 8 x 5 cm were received 17

18 Dominant eosinophilic material morphologically consistent with amyloid Patchily incarcerated plasma cells, vastly out proportioned by the amyloid 18

19 H&E : surgical specimen 19

20 H&E : surgical specimen 20

21 H&E : surgical specimen 21

22 H&E : surgical specimen 22

23 Congophilia 23

24 Thioflavin -T Congo Red - Polarised 24

25 CD138; CD38 25

26 LCA ; CD 20 26

27 IHC kappa light chain 27

28 IHC lambda light chain 28

29 Final Pathology - Plasma cell neoplasm with kappa light chain monotypia and associated AL amyloidotic tumor Recommended MDT re discussion Adjuvant: IGRT to right hilar area and adjacent lung; 50 Gy in 25 fractions to GTV and 45 Gy in 25 fractions to CTV and PTV 29

30 Discussion, further considerations and implications Amyloid (osis) - heterogeneous group of diseases - deposition of congophilic amyloid fibrils in the extracellular matrix of tissues and organs. 95% of amyloid - fibril proteins 5% serum amyloid P component + other glycoproteins 30

31 Fibril proteins isoluble / resistant to being scavenged - improper folding of soluble precursors - proteins with a normal amino acid sequence prone to misfolding when produced in excessive amount (eg, immunoglobulin light chains, serum amyloid A, and wild-type transthyretin) - Misfolding may also result from an abnormal amino acid sequence (eg,transthyretin variants) 31

32 31 fibril proteins identified in humans Amyloidoses named after these fibril proteins systemic AL (formerly primary), systemic AA (formerly secondary), systemic wild-type ATTR (formerly age-related or senile systemic), systemic hereditary ATTR amyloidosis (formerly familial amyloid polyneuropathy) 32

33 3 Clinicopathologic forms of amyloidosis Lung: - diffuse alveolar-septal amyloidosis - nodular pulmonary amyloidosis - tracheobronchial amyloidosis 33

34 Diffuse alveolar-septal amyloidosis As a rule = manifestation of systemic amyloidosis (rare exceptions, with no evidence of a systemic disease) most often diffuse alveolar-septal amyloidosis - a postmortem finding 34

35 most common association - systemic AL amyloidosis (rare cases caused by systemic AA, systemic wildtype ATTR, and systemic hereditary ATTR amyloidosis have been reported) 35

36 Recap- Systemic AL amyloidosis (formerly primary amyloidosis) - monoclonal plasma cell proliferative disorder - monoclonal immunoglobulin light chains are deposited in tissues - MGUS, may precede this; may be associated with MM and WM 36

37 International Myeloma Working Group criteria: (1)presence of a systemic amyloid-related syndrome (2)proof of amyloid deposition in any tissue by a Congo red stain (3)proof that the deposits are composed of immunoglobulin light chains (4)evidence of a monoclonal plasma cell proliferative disorder. Rx - usually treated with CTx followed by autologous stem cell transplant 37

38 Nodular pulmonary amyloidosis (aka nodular parenchymal amyloidosis) 1 or more tumefactive amyloid deposits involving the lungs. It usually represents localized AL or AL /AH (mixed immunoglobulin light chain/heavy chain) amyloidosis 38

39 Localized AL amyloidosis is not unique to the lungs and the tracheobronchial tree It can also occur at other sites including the larynx, urinary bladder and colon. 39

40 In the past NPA and primary pulmonary lymphoma with amyloid production were considered different processes Current opinion favours NPA (most cases) result from an underlying LPD Within spectrum of EMZL (MALT lymphoma) underlying LPD might be extremely subtle 40

41 Morphologic - D/D - pulmonary hyalinizing granuloma - thick collagen bundles arranged in lamellae - Amyloid-like nodules - composed of nonamyloid light chains (typically kappa), Congo Red negative. Usually - LCDD with renal involvement and an underlying monoclonal plasma cell proliferative disorder 41

42 Tracheobronchial amyloidosis: Amyloid deposition in segments of the tracheo - bronchial tree. Most cases - localized AL amyloidosis least common (100 cases) submucosal vessels + in most cases plasma cells, foreign body type giant cells, calcifications, and ossification common 42

43 Amyloid subtyping - reveals monoclonal immunoglobulin light chains Lambda light chain detection > kappa PCR may or may not detect a localized clonal expansion of B cells 43

44 Three patterns - Proximal - Mid - Distal airway disease Dyspnea, cough, hemoptysis, or hoarseness. Bronchoscopy with transbronchial biopsy for Dx CT/ PET for determining the extent 44

45 PFT proximal airway disease - decreased airflows distal airway disease - normal airflows Proximal and severe mid airway disease can lead to severe airway compromise Tx laser or forceps debridement Surgical excision EBRT 45

46 Evolution - Recurrence is common post debulking - 30% die of the disease if no adjuvant RT - EBRT offer better outcomes 46

47 Contextualisation with broncho - pulmonary LPDs - Primary pulmonary LPDs / small lymphocytic lesions - Large cell or high grade lesions - Lymphomatoid granulomatosis 47

48 Benign lymphoproliferative disorders Follicular bronchitis / bronchiolitis Localized/nodular lymphoid hyperplasia ("pseudolymphoma") Lymphoid interstitial pneumonia 48

49 Malignant lymphoproliferative disorders NHL EMZL- (MALT lymphoma) Intermediate/high grade lymphoma Lymphomatoid granulomatosis Intravascular lymphomatosis 49

50 Hodgkin lymphoma Secondary pulmonary lymphoma / leukemia Miscellaneous conditions PTLDs EBV related lymphoid infiltrates in immunocompromised patients 50

51 Tumefactive growth Lymphangitic growth Lymphoepitheli al complexes Follicles with germinal centers Cytology FB LIP NLH MALT absent absent present present limited to bronchovascular bundles absent absent present rare rare rare common main finding, broncho vascular bundles typical of benign follicles focal finding, broncho vascular bundles polymorphic, including plasma cells localized finding, randomly distributed polymorphic including typical benign follicles and plasma cells focal with mantle zone "colonization", randomly distributed monomorphic including centrocytelike/ monocytoid small lymphocytes ± plasmacytic differentiation /plasma cells

52 EMZL B-cell lymphoma (MALT lymphoma) 80% of primary pulmonary lymphomas Dense lymphoid infiltrate - tumefactive + lymphangitic growth patterns Cf. diffuse forms of PLH the infiltrate is expansive, with microscopic or macroscopic nodules Obliteration of underlying lung structures 52

53 vascular infiltration ("angiitis") monomorphic scant or clear cytoplasm Plasmacytic differentiation 30-40% cases (PLs or mature). 53

54 Secondary changes in MALT - L - organizing intraluminal fibrosis / BOOP - non-necrotizing granulomas (cf. granulomatous infection, HP, sarcoid) - Amyloid 54

55 Site t(11;18) t(1;14) t(14;18) t(3;14) * t(neg) Stomach 22% >1% 3% - 74% Orbit 7% 0% 12% 20% 61% Salivary gland 2% 1% 5% - 92% Lung 42% 8% 6% - 44% Skin 4% 0% 8% 10% 78% Intestine 15% 10 0% - 75% t(11;18)(q21;q21), results in API2-MALT1 gene 55

56 56

57 - PPLs - 0.3% lung neoplasms, <1% of all lymphomas,3.6% of extranodal lymphomas - Median 60 years 35% asymptomatic (usually low-grade) Up to 30 % of patients have an associated autoimmune disease (Sjogren s) 57

58 Approximately 70% of cases are EMZL Diffuse / interstitial pattern, + intact or disrupted reactive lymphoid follicles Lymphoepithelial lesions (bronchial or bronchiolar) Amyloid and monoclonal paraproteins (43%) commoner in lung, than other sites 58

59 Main problem low grade MALT lymphoma vs chronic inflammatory processes with lymphoid hyperplasia Favour MALT - L B cells with morphology of marginal zone cells in a diffuse pattern outside follicles B- LELs 59

60 Course - Relapse lung / at other MALT sites (especially stomach, salivary glands,lymph nodes) - transformation to DLBCL Overall, survival is good regardless 60

61 Plasma cell differentiation subtle to extreme variable proportion in small B cell lymphomas (SBLs) expected (lymphoplasmacytic lymphoma (LPL) infrequent (mantle cell lymphoma (MCL) 61

62 Not always clear-cut, some cases may need to be diagnosed as a small B cell lymphoma with plasmacytic differentiation with D/d provided NGS - MYD88 L265P mutations in the vast majority of LPLs and relatively few other SBLs 62

63 MYD88 L265P mutations: vast majority of LPLs /WM subset of IgM but not IgG or IgA MGUS not in plasma cell myelomas (PCMs) even of IgM type 63

64 MYD88 only if LPL is a strong possibility and pathology not definitive A positive result should lead to a diagnosis of LPL 64

65 FL (LMO-1, HGAL-1, BCL2 translocation FISH)- plasmacytic differentiation varies from prominent plasma cells seen in the HE sections to cases only recognized with the aid of immunohistochemical stains and not necessarily with CD138 expression 65

66 MZLs (with plasmacytic differentiation) IRTA-1 expression is reported to help identify NMZL, the antibody is not commercially available Difficult diagnoses - especially if extreme plasmacytic differentiation mutational studies helpful 66

67 MALT lymphomas can mimic IgG4-related disease can arise in the setting of IgG4-related disease Important to establish whether IgG4+ plasma cells are light chain class restricted 1/3 MALT lymphomas are reported to be IgG4 67

68 ? Lymphoma with complete plasmacytic differentiation /? plasma cell neoplasm Plasmacytic differentiation can be extreme and total Eg : The present case? Extramedullary plasmacytoma, with AL amyloid? EMZL with extreme plasmacytic differentiation can not be excluded - definitive diagnoses are sometimes beyond our reach 68

69 Extracellular Para protein deposition whole Ig molecules amyloid light-chain (AL) amyloidosis crystalized Ig in reactive histiocytes (CSH)) 69

70 Proteomic analysis: localized AL amyloidosis (MALT) Ig heavy chain is present in the amyloid plaque in systemic AL amyloidosis, Ig light chains without a heavy-chain component are deposited at distant sites 70

71 Select biobliography Kyle RA. Amyloidosis: a convoluted story. Br J Haematol. 2001;114(3): Berk JL, O Regan A, Skinner M. Pulmonary and tracheobronchial amyloidosis. Semin Respir Crit Care Med. 2002;23(2): Dacic S, Colby TV, Yousem SA. Nodular amyloidoma and primary pulmonary lymphoma with amyloid production: a differential diagnostic problem. Mod Pathol. 2000;13(9): Khoor A, Colby T V. Amyloidosis of the Lung. Arch Pathol Lab Med. 2017;141: ;doi: / arpa ra Int J Radiation Oncol Biol Phys, Vol. 92, No. 1, pp. 11e31,

72 THANK YOU 72