Sjogrens Syndrome and Lymphoma

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Sjogrens Syndrome and Lymphoma
Rheumatology Rounds SMH
Dr. Nicole Chau PGY1 November 22, 2005
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Objectives

• To review diagnostic and clinical features of
  Sjogrens
• To summarize the literature on incidence and
  prevalence of lymphoma in Sjogrens patients
• To identify risk factors for development of
  lymphoproliferative disorders
• To identify time frame of development of lymphoma
  
• To identify risk factors for mortality

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Background Case

• 1994 57yo F
• Left parotid enlargement, dry mouth, low grade
  fever, arthralgias thought to have sialadenitis,
  given antibiotics with some relief
• Lymphadenopathy investigations normal

4
Background Case

• 1997 Jan
• Admit for low grade fever/chills, sweats, dry
  mouth
• CT CAP normal, CT head neck showed LN, normal
  abdo U/S, BM Bxreactive
• Hb 92, MCV 72, WBC 5 (10 lympho), CD4 90, plt
  118, ESR 60, C3 0.73, C4 0.02

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Background Case

• 1997 Mar
• Admit to ICU for MSOF (renal, GI, cardiac, heme)
  pulmonary edema
• Hb 90s, WBC 18 left shift 2 lympho, plt 200,
  bld filmmicroangiopathic hemolytic picture
• Cr 125 w/ heme granular casts 3 protein,
  cryoglobulins, hypogammaglobulinemia

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Background Case

• 1997 June
• Sjogrens dx, sicca, RF , weakly ANA, Ro, La
• Cryoglobulinemia confirmed on renal bx
• 1997 Oct
• Worsening renal function, started
  cyclophosphamide 100mg OD

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Background Case

• 2001 May
• Started Imuran, (Prednisone induced myopathy)
• 2002 2003
• Recurrent enlarged submandibular LN RgtL,
  Odynophagia resolved with antibiotics

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Background Case

• 2003 Nov
• Left submandibular swelling 2.5 x 3cm
• Firm enlarged parotids with discreet mass in left
  tail
• 2004 Jan FNA inflammatory cells/indeterminate
• 2004 Jan FNA inadequate sample
• 2004 Feb FNA inflammatory cells
• 2004 Mar FNA inflammatory cells
• Mass continues to enlarge (gtbaseball size).

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Background Case

• 2004 Mar
• Admitted to ENT for IV clinda and work up of left
  level 2 neck mass
• CT shows large mass w/ necrotic centers, multiple
  nodes gt1cm
• Excisional Bx large cell lymphoproliferative
  process c/w anaplastic plasmacytoma
• 2004 April
• Gallium scan showed multiple disease sites in
  bilat axilla, intra-abdominal LN
• BM asp bx normal, no increased Ig
• 2004 May Aug
• Completes CHOP

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Sjogrens Syndrome

• 1892 Mickulicz syndrome
• 1933 Henrik Sjogren, Danish opthalmologist
  keratoconjunctivitis sicca
• Annual incidence 4/100 000 population
• Prevalence 0.5 among adults
• 9/10 female

Ann Rheum Dis 199756521-5 Scand J Rheumatol
20043339-43
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Sjogrens Syndrome

• Systemic autoimmune disorder characterized by
  lymphocytic infiltration of exocrine glands,
  especially lacrimal and salivary glands

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Defining Sjogrens

• Criteria for international consensus and
  classification
• NOT required for clinical diagnosis
• At least nine different criteria sets proposed in
  past 20 years
• Primary vs Secondary

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Lymphoctyic Infiltrates
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Labial Salivary Gland Biopsy

• To confirm diagnosis of primary Sjogrens
  syndrome
• Labial salivary gland biopsy score of gt1
  lymphocytic focus/4mm2
• False positive with SLE, AIDS, myasthenia gravis
• False negative with corticosteroids and smoking
• New QIH method has 93 sensitivity
• 396 patients, reviewed for diagnosis by 5
  experts, changed diagnosis from indefinite to
  definite in 31
• Van Woerkom JM. Rheum 2005 Nov 15 (Epub
  ahead of print)
• May make a diagnosis of lymphoma (case report)
• B cell MALT lymphoma diagnosed by labial minor
  salivary gland biopsy in patients screened for
  Sjogren's syndrome.
• Van Mello NM et al. Ann Rheum Dis 2005
  Mar64(3)471-3

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Non-exocrine Features of Sjogrens

• MSK arthritis, arthralgia (50)
• Cutaneous Vasculitis
• lower extremity purpura (palpable/nonpalpable)
• urticarial
• digital ulcers
• erythema multiforme
• livedo
• Raynauds
• Resp sinusitis, ILD, alveolitis
• Endocrine autoimmune thyroiditis

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Non-exocrine Features of Sjogrens

• GI dysphagia, PBC, chronic hepatitis, celiac
• Renal interstitial nephritis, type 1 RTA
• CNS (20) neuropsychiatric, peripheral
  neuropathy
• Heme
• anemia of CD
• hemolytic anemia
• leukopenia, thrombocytopenia
• type II cryoglobulins
• Lymphoma (First described in 1963, 3 cases of
  lymphoma and one Waldenstroms macroglobulinemia
  out of 58 pts with sicca syndrome)

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Sjogrens Lymphoma

• Chronic excess B cell stimulation
• Salivary, lacrimal and cervical lymph nodes are
  the main sites of monoclonal B cell proliferation
  also of SS related lymphoma
• Most lymphoma arises from reactive infiltrate
  called lymphoepithelial sialedenitis (aka benign
  lymphoepithelial lesion)

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Monoclonal B Cell Proliferation Precedes Clinical
Onset Of NHL

• Immunophenotyping showed evidence of light chain
  restriction in B cells infiltrating salivary
  glands
• Speight PM. Eur J Cancer B Oral Oncol
  199430B(4)244-7
• Immunogenotyping detected monoclonal Ig light or
  heavy chain rearrangements in labial salivary
  gland biopsies using PCR
• Jordan RC. Int J Hematol 199664(1)47-52
• Circulating monoclonal immunoglobulins were
  detected in nearly 20 of patients with primary
  SS Brito-Zeron P. Medicine 200584(2)90-97

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Neoplastic Transformation

• Mechanism unclear, multi-step process
• Chronic antigenic stimulation for clonal
  selection expansion
• Monoclonal proliferation suggests dysregulation
  of B cell system likely predisposing to malignant
  transformation
• Dysregulation cell cycle check points and
  apoptosis

Tapinos NI. Arthritis Rheum 1999421466 Mariette
X. Leuk and Lymph 199933(1-2)93-99
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Spectrum of Malignant Lymphoproliferation

• Circulating monoclonal immunoglobulins
  (monoclonal gammopathy)
• Free light chains
• Mixed monoclonal cryoglobulins
• Non-Hodgkins lymphoma
• Extranodal marginal zone B cell lymphoma (MZL) of
  MALT (mucosa associated lymphoid tissue)

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Clinical Presentation

• Extraglandular spread to lung, kidney, lymph
  nodes, skin, bone marrow
• Clinically indistinguishable between lymphoma vs
  pseudolymphoma

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Pseudolymphoma

• Pleomorphic cells but not meeting malignant
  criteria
• May present as
• enlarged parotids
• lymphadenopathy (regional and generalized)
• hepatosplenomegaly
• pulmonary infiltrates
• vasculitis
• hypergammaglobulinemia

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What is the risk?
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First Study To Assess Magnitude Of Risk

• Kassan et al. followed 142 pts between 1954 to
  1975, average f/u 8.1 years
• 7 cases of NHL between 6 mos to 13 years after
  admission
• 43.8 times incidence expected in general
  population at the time (plt0.01)
• Risk of malignant lymphoma in pts with SS is 6.4
  cases per 1000 per year

Kassan et al. Ann Intern Med 197889888-92
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Risk Of Developing Lymphoma
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Lymphoma And Other Malignancies In Primary
Sjogrens Syndrome.A Cohort Study On Cancer
Incidence And Lymphoma Predictors. Theander E
et al.Ann Rheum Dis 2005 Nov 10 epub ahead of
print

• Prospective cohort of primary Sjogrens patients
  to analyze risk of general malignancy and
  lymphoma
• Mean follow up 8 years (range 1 month to 19
  years), total observation 2464 years in AECC SS
  group
• 507 patients with pSS as per Copenhagen, European
  or AECC

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Lymphoma And Other Malignancies In Primary
Sjogrens Syndrome.A Cohort Study On Cancer
Incidence And Lymphoma Predictors. Theander E
et al.Ann Rheum Dis 2005 Nov 10 epub ahead of
print

• In patients with primary Sjogrens, there is a 16
  fold increased risk of lymphoma
• No significant increased risk of developing
  malignancy in patients with primary Sjogrens
• No increased risk for patients with sicca
  symptoms alone to develop lymphoma

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Sjogrens Associated With Increased Risk Of
Non-Hodgkins Lymphoma
Theander et al. Ann Rheum Dis 2005 Nov 10
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Elevated Incidence Of Hematologic Malignancies In
Patients With Sjogrens Compared With Rheumatoid
Arthritis

• National Finish Registry, cohort of
• 676 patients with Primary Sjogrens disease
• 709 patients with Secondary Sjogrens disease
• 9469 patients with Rheumatoid Arthritis

Kauppi M et al. Cancer Causes Control
19978201-204
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Time to Diagnosis of Lymphoma

• Conflicting results
• Some studies suggest increased risk over time
• Lymphoproliferative disease probability
• 2.6 at 5 years and 3.9 at 10 years

Ioannidis JP et al. Arthritis and Rheum
200246(3)741-747
32
Risk Of Lymphoma Increased With Time After
Diagnosis Of Primary Sjogrens (mean 8 yrs)
Theander et al. Ann Rheum Dis 2005 Nov 10
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Malignant Non-Hodgkins Lymphoma Types

• Variable
• follicle center, lymphoplasmacytoid, DLBC, MALT
• Mostly low grade B cell
• 46-56 are MALT
• Mostly high grade DLBC

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Lymphoma Types

• 26/27 were NHL (B cell origin in 24, T cell
  origin in 2) 8 low grade
• 6 mucosa associated lymphoid tissue type (MALT)
• 2 follicular mixed type
• 18 intermediate type
• 10 diffuse medium, 4 diffuse large
• 2 angioimmunoblastic T cell
• 1 follicular medium type, 1 T cell rich B cell
  type
• 1/27 was Hodgkins lymphoma
• 14/27 had stage I and II localized disease
• Mean age of onset of Sjogrens 51.3 yrs, disease
  duration 3.4 yrs JCAT 2003 Jul-Aug27(4)517-24

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Clinical Signs Associated With Lymphoma
Development

• Salivary gland enlargement
• Lymphadenopathy
• Splenomegaly
• Palpable purpura
• Cutaneous vasculitis
• Low grade fever
• Leg ulcers
• Peripheral neuropathy
• History of cytotoxic therapy/parotid irradiation

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Laboratory Predictors Of Lymphoma Development

• Anemia
• Lymphopenia
• Low CD4 T lymphocytes, low CD4/CD8 ratio
• Mixed cryoglobulinemia
• Low C3
• Low C4

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Ramos-Casals M et al. Rheumatology
200544(1)89-94
38
Hypocomplementemia Is Associated With Systemic
Manifestations, Lymphoma And Death

• Hypocomplimentemia detected in 24 of 336
  patients with primary Sjogrens as per ECE
  criteria, prospective follow up since 1994 of 218
  patients
• Low C4 levels
• associated with higher prevalence of peripheral
  neuropathy, cutaneous vasculitis, RF,
  cryoglobulins compared with normal C4 levels
• Are an independent predictor of lymphoma in new
  and prevalent cases

Ramos-Casals M et al. Rheumatology
200544(1)89-94 Ioannidis JP et al. Arthr and
Rheum 200246741-7 Theander E et al. Arthr and
Rheum 2004501262-9 Tzioufas AG et al. Arthr
and Rheum 199639767-72
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Hypocomplementemia Is Associated With Systemic
Manifestations, Lymphoma And Death

• Lower survival in patients with lower complements
  (c3 or c4 or CH50) at baseline
• Patients with low C4 levels had increased
  cause-specific standardized mortality ratio for
  lymphoproliferative disease compared with
  patients with normal C4 levels
• Recommend to check complements at diagnosis and
  follow up of primary Sjogrens to serve as
  predictor for outcomes

Ramos-Casals M et al. Rheumatology
200544(1)89-94
40
CD 4 T Lymphocytopenia Is Associated With
Development Of Lymphoma

• Theander et al. Ann Rheum Dis 2005 Nov 10
• Lymphocytopenia Mandl Tet al. J Rheumatol.
  200431(4)726-8 Idiopathic CD 4 T lymphocyte
  counts lower among anti-SSA antibody seropositive
  SS patients compared to correlating seronegatives
  and primary Sjogrens sundrome.

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Low Complement And Low CD4
Theander et al. Ann Rheum Dis 2005 Nov 10
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• Independent predictors of developing
  lymphoproliferative disease
• parotid enlargement (HR 5.21, CI 1.76-15.4,
  p0.003)
• palpable purpura (HR 4.16, CI 1.65-10.5, p0.002)
  
• low C4 (HR 2.4, CI .99-5.83, p0.052)
• if one of 3 of the above (n367) at onset then
  9.08 higher risk of LPD development than those
  who did not

Ioannidis JP et al. Arthritis and Rheum
200246(3)741-747
44

• Ioannidis JP et al. Arthritis and Rheum
  200246(3)741-747

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Mortality And Lymphoma In PSS

• Standardized mortality ratio 1.15 (CI 0.86-1.73)
• Over 700 patients with primary SS
• Follow up max 18 years (mean 6 years)
• 39 deaths (7 due to lymphoma) close to 20 of
  deaths due to lymphoma
• ALL cases of lymphoma that resulted in death
  occurred in patients who presented with low C4 or
  palpable purpura at their FIRST study visit

Ioannidis JP et al. Arthritis and Rheum
200246(3)741-747
46
Mortality And Lymphoma In PSS

• Mixed results given diversity of patient
  population follow up
• Tumour grade predicts mortality
• Median survival 3.3 yr for high grade Ioannidis
  JP et al. Arthritis and Rheum 200246(3)741-747
• Median survival low grade 6.33 yrs, intermediate
  or high grade 1.833 yrs
• Worse overall survival if
• B symptoms (RR 9.2, p 0.017)
• tumour size gt7 cm (RR7.7, p0.046)
• histo class int-high (RR4.1 p 0.067)

Voulgarelis et al Arthritis Rheum 1999421765-72
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Mortality

• Patients with secondary Sjogrens had increased
  mortality compared with those with primary
  Sjogrens (p 0.04)
• Patients with primary Sjogrens had no increased
  mortality to general population
• Martens PB. Survivorship in a Population Based
  Cohort of Patients with Sjogrens Syndrome,
  1976-1992 J Rheumatol 1999261296-300

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Summary

• Increased risk of non-Hodgkins lymphoma
• previously thought to be 44 fold
• now thought to be 16 fold
• Clinical predictors include
• salivary gland swelling
• lymphadenopathy
• cutaneous vasculitis
• low grade fever
• peripheral neuropathy

• Laboratory predictors include
• low complements
• lymphopenia
• low CD4, low CD4/CD8
• cryoglobulinemia

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Recommendations for Screening for Lymphoma

• No formal guidelines
• Consider
• Confirming diagnosis of primary Sjogrens
  syndrome
• Role of labial salivary gland biopsy
• Measuring complements, lymphocytes, CD4 at
  diagnosis f/u
• Low threshold for imaging and biopsy (FNA,
  excisional) in patients with clinical features of
  salivary gland enlargement, lymphadenopathy,
  cutaneous vasculitis, low grade fevers

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Future Directions
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Future Directions

• Understanding concepts in Sjogrens etiology and
  pathogenesis
• What is the extent of shared etiology of
  cryoglobulinemia, hypocomplementemia, B cell
  activation and CD4 T cell depletion?
• Ramos-Casals et al. Triple association between
  Hepatitis C Virus infection, systemic autoimmune
  diseases, B cell lymphoma. J Rheum 200431495-9
• B Cell Activating Factor (BAFF(Blys)) regulates B
  lymphocyte proliferation and survival, associated
  with B cell hyperactivity, BAFF levels correlated
  with circulating Ab (IgG, RF, anti-Ro and
  anti-La), found in T cells infiltrating labial
  salivary glands in SS

Ramos-Casals M, Font J, Primary Sjogrens
syndrome current and emergent aetiopathogenic
concepts. Rheumatology 2005441354-1367 Lavie F
et al. Expression of BAFF (BLyS) in T cells
infiltrating labial salivary glands from patients
with Sjogren's syndrome . J Path
2004202(4)496-502 Mariette X et al. Ann Rheum
Dis 200362168-71
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Thank you