Case 4 History 58 yo man presented with prox IP joint swelling 2 months later pain and swelling in multiple joints Chest radiograph: bi-basilar basilar infiltrates suggestive of pulmonary fibrosis Open lung biopsy
Case 4 Diagnosis Non-specific interstitial pneumonia (NSIP) occurring in association with rheumatoid arthritis
Pleuropulmonary Manifestations of Rheumatoid Arthritis Pleura: pleuritis, effusions Nodules Airways: bronchiectasis, BOOP, OB Vessels: hypertension, vasculitis Interstitium: NSIP, UIP, L Hyp, DAD, BOOP Drug-induced
Diagnosis of Lung Disease Associated with Connective Tissue Disorders - Challenges Spectrum is broad Few of the histologic lesions are unique May be overlapping pathologic patterns Lung involvement may precede onset of full blown disease? Therapy related direct effect opportunistic infection
Interstitial Disease among 40 RA patients with OL Bx * (%) BOOP 6 (22) UIP 5 (18) LIP/LH 5 (18) NSIP 5 (18) DAD 2 (18) other ILD 4 (15) Total 27 * 13 had RA nodules Yousem SA, Colby TV. Am Rev Resp Dis 1985
Usual Interstitial Pneumonia Pathologically Variegated Process Normal lung Old fibrosis with dense collagen deposition (and honeycomb change) Foci of fibroblast proliferation Architectural Distortion with Bronchiectasis Interstitial inflammation
UIP
Usual Interstitial Pneumonia
UIP
Fib Foci in UIP * * *
* * Fib Foci in UIP *
Non-specific Interstitial Pneumonia A temporal and geographically homogeneous chronic interstitial pneumonia with variable degrees of inflammation and fibrosis but without significant architectural distortion (honeycomb change), granulomatous inflammation or intra-alveolar macrophage accumulation.
NSIP Underlying Diseases and Associations Connective tissue diseases RA, SLE, PM/DM, PSS, SjS Organic antigen exposure Birds, wood stove, grain dust, industrial exposure (paper), vet worker, jacuzzi Autoimmune diseases PBC, Hashimoto s, acute GN Medications 16% Hydralazine, gold, penicillamine 16% Idiopathic 60% 5% 3% Katzenstein and Fiorelli: Am J Surg Pathol 18:136, 1994 CP1040982-1
NSIP
Nonspecific Interstitial Pneumonia/ Fibrosis - Histologic Findings (n = 64) Temporally uniform Patchy, 55% Diffuse, 45% Bronchiolocentric 28% Granulomas 8% Focal BOOP-like areas 48% Katzenstein, Fiorelli.. Am J Surg Pathol 1994, 18:136
NSIP/F - Histopathologic Groups Group 1: Cellular IP, minimal fibrosis (n = 31) Group 2: Cellular IP, moderate fibrosis (n = 24) Group 3: Dense fibrosis/scarring (n = 9) Katzenstein, Fiorelli.. Am J Surg Pathol 1994, 18:136
Cellular NSIP
Cellular NSIP
Cellular and Fibrotic NSIP
Cellular and Fibrotic NSIP
Fibrotic NSIP
Fibrotic NSIP
Survival Following Diagnosis of 100 IPF 80 Survival (%) 60 40 20 0 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 Years following diagnosis Others Nonspecific UIP Bjoraker J et al: Am J Resp Crit Care Med, 1998 CP1095047-2
Nonspecific Interstitial Pneumonia Outcomes in Published Studies 100 Free of disease Alive with disease Dead of disease 80 % 60 40 20 0 Katzenstein 1994 Park et al, 1995 Cottin et al, 1998 Nagai et al, 1998 Daniil et al, 1999 Travis et al, 2000 Nicholson et al, 2000 CP1061069-56
80 60 Nonspecific Interstitial Pneumonia Distribution of Subtypes and Honeycomb Change in Published Studies Cellular NSIP (Group I) Fibrotic NSIP (Group III) % HNCB % 40 20 0 *Not analyzed Katzenstein, 1994 * * Cottin et al, Nagai et al, Travis et al, Nicholson et al, 1998 1998 2000 2000 CP1061069-57
Fibroblast Foci (FiFo) ) in NSIP N % FiFo Katzenstein 64 24 (rare foci) Nagai 31 - Travis 29 55
UIP: Histologic Study of Biopsy and Explant Specimens Areas resembling NSIP commonly occur in a background of otherwise typical UIP. Katzenstein et. al. Am J Surg Pathol 2002;26, 1567
Histopathologic Variability in UIP and NSIP 109 patients with UIP and NSIP who underwent biopsy 2 lobes Concordant UIP (UIP + UIP) 51 NSIP (NSIP + NSIP) 30 Discordant UIP (UIP + NSIP) 28 Flaherty et al AJRCCM 2001;164: 1722
Histopathologic Variability in UIP and NSIP 1.0 NSIP 0.8 Cumulative proportion surviving 0.6 0.4 0.2 Concordant UIP Discordant UIP 0.0 Flaherty et al: AJRCCM, 2001 0 1 2 3 4 5 6 7 8 9 Years CP1047154-2
Inter-observer variation between pathologists in diffuse lung ds Cases referred to Brompton for consult- ation between Jan 96-Dec 97, n=133 circulated to 10 UK pulmonary pathologists Slides, age and gender, site of biopsy Diagnosis weighted kappa UIP 0.59 NSIP 0.40 Mean OP (BOOP) 0.57 0.58 EAA 0.47 Sarcoidosis 0.86 Nicholson AG et al Thorax 2004;59:500-505 505
Difficult UIP Diagnosis Biopsy and Explanted Lungs Compared, n = 20 Katzenstein ALA. Am J Surg Pathol 2002; 26:1567 1. Superimposed DAD 2. Superimposed BOOP 3. Extensive Honeycomb on Biopsy 4. Prominent NSIP-like areas with no or focal honeycomb
Role of the Pathologist in Diagnosing NSIP and UIP on Surgical Biopsies Bx = NSIP You sure? patchwork? HNCB? fib foci? no traps?? I m pretty sure... HRCT = UIP?
Role of HRCT in Separating UIP/IPF from NSIP HRCT Dx Histologic Diagnosis UIP NSIP Total UIP* 27 0 27 Indeterminate 20 5 25 NSIP* 26 (59%) 18 44 *includes definite and probable dx Flaherty et al. Thorax 2003; 58: 143
indeterminate UIP HRCT UIP UIP-NSIP UIP-UIP Path Path + HRCT NSIP NSIP NSIP-NSIP UIP/IPF Role of HRCT in Separating from NSIP (A) HRCT dx of NSIP (dotted line), indeterminate (dashed line), and UIP (solid line), p=0.01 (B) Pathology dx of NSIP (dotted line) and UIP (solid line), p=0.0006 (C) Pathology NSIP and HRCT indeterminate or NSIP (dotted line), pathology UIP and HRCT indeterminate or NSIP (dashed line), and pathology UIP and HRCT UIP (solid line), p=0.001 Flaherty et al. Thorax 2003; 58: 143
Role of the Pathologist in Diagnosing UIP or NSIP in Surgical Biopsies Bx = NSIP You sure? patchwork? HNCB? fib foci? no traps?? I m pretty sure. Probably UIP YES HRCT = UIP? NO NSIP
Interstitial Disease Associated with Connective Tissue Disease What is the frequency of subcategories? Does the histology differ compared to those with idiopathic disease of same subcategory? Does prognosis differ compared to patients with idiopathic disease?
Cellularity of RA assoc vs Idiopathic UIP and NSIP Turesson et al, submitted
Cellularity of RA Turreson assoc vs Idiopathic UIP and NSIP Turesson et al, submitted
Interstitial Disease Associated with Connective Tissue Disease What is the frequency of subcategories? Does the histology differ compared to those with idiopathic disease of same subcategory? Does prognosis differ compared to patients with idiopathic disease?
Mortality in Patients with Lone UIP and RA % mos Lone UIP Bjoraker et al 63 24 RA/UIP Yousem et al 60 20
Survival Amongst Patients with 1.0 LCFA and FA-CTD 0.8 General population Survival 0.6 0.4 LCFA FA-CTD 0.2 0 1 2 3 Years Hubbard and Venn: Rheumatology 41:676, 2002 CP1095047-1
Survival probability 1.0 0.8 0.6 0.4 0.2 CTD/UIP vs IPF/UIP CTD/UIP IPF/UIP 0.0 0 1 2 3 4 5 6 7 8 Years Flaherty et al: Am J Resp Crit Care Med 167:1410, 2003 CP1137209-1
4 IPF/UIP Fibroblast Foci CTD/UIP Fibroblastic foci score 3 2 1 0 0 50 100 150 0 2 4 6 8 10 Lobes Lobes Flaherty et al: Am J Resp Crit Care Med 167:1410, 2003 CP1137209-2
Case 4 Follow-up Treated with immunosuppression including steroids Lung function remained stable x 6 years Died of PE following tx for lymphoma
On to Case 5