Case 13-2008-Rheum Arthritis, Lymphadenopathy

7/28/2019 Case 13-2008-Rheum Arthritis, Lymphadenopathy

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Clinicopathological ConferenceLymphoma Conference

Case 13-2008

Nikhil C. Munshi, M.D.

J erome Lipper Myeloma Center, DFCI

Boston VA Healthcare System

Subba Digumarthy, M.D.

Radiology

Aliyah Rahemtullah, M.D

Pathology


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"A 47-year-old man with rheumatoidarthritis and generalized

lymphadenopathy"

Presentation of Case

Viviany Taqueti, HMS IV


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46yo M seen by hematologist-oncologist because

of lymphadenopathy and anorexia for one month

Recent PMH:

Rheumatoid Arthritis

- Diagnosed 3 1/2 yrs earlier

- AM stiffness, joint pain, swelling,

decreased range of motion- Elevated RF, ANA, RNP, ENA

- Controlled on prednisone, NSAIDs

methotrexate, folic acid, leflunomide

Ref 3.5 yrs

prior

RF


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Recent PMH (cont):

Subacute Cutaneous Lupus Erythematosus

- 19 mo earlier, cutaneous lesions on sun-exposed areas

- diagnosed on biopsy

- hydroxychloroquine added, methotrexate discontinued

Oral candidiasis, recurrent

- 1 yr earlier, discontinued corticosteroids

Low leukocyte count, intermittent and fluctuating

3.3 yrs earlier 8 mo 4 mo 5 d

WBC (4500-11000) 5200 2900 3600 8800


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Neutropenia 3 mo earlier, seen by hematologist for neutropenia

felt well, arthritis asymptomatic occasional GERD relieved by pantoprazole

PMH:

tonsillectomy in childhood

?Juvenile rheumatoid arthritis

18 yo, pain and swelling in elbow, ankles, resolved

?Ankylosing spondylitis

no back pain, iritis, aphthous ulcers, dysuria or rash

s/p splenectomy and cholecystectomy 32 yo, splenomegaly (19cm) found incidentally

400 g spleen, fibrocongestion, reactive lymphoid hyperplasia

BM biopsy normal

Pneumococcal vaccine given


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Neutropenia (cont.)

No drug allergies

Medications

leflunomide, meloxicam, FA, hydroxychloroquine, pantoprazole

PE

diffuse erythema over face and chest

I/IV early diastolic murmur, left sternal border Laboratory test results (see Table)

Howell-Jolly bodies on peripheral smear, normal flow cytometry

Negative serologies for HIV, Hep A, B, C

Imaging

No evidence of accessory spleen on abdominal scan

Management

Neutropenia thought to be related to medications

Advised to discuss possible changes in therapy with rheumatologist


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HPI: Diffuse Lymphadenopathy (LAD)

1 mo before evaluation, diffuse LAD developedgradually in neck, axillae, groin

- with sore throat and loss of appetite, but no weight loss

- no shortness of breath or chest pain

1 wk before evaluation, fatigue, nausea, bloating, loosestools, cough productive of white sputumdeveloped

5 d before evaluation, seen by PCP:

PE: - T 37.3 C, BP 118/70, HR 108, O2 Sat 98% RA- White lesions on lateral tongue

- Diffuse tender lymphadenopathy: R submandibular (2cm),

A/P cervical, axillary, bilateral R>L. No inguinal nodes.


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Diffuse Lymphadenopathy (cont.)

Laboratory test results: see Table

Management: oral nystatin was prescribed

Next day: returned w/ wheezing, nasal discharge,maxillary sinus tenderness, bulging tympanic membranes.

LAD slightly decreased.

Imaging


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Radiology Studies

Subba Digumarthy, M.D.


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Shows multiple enlarged lymph nodes (arrows) in both

axillae.


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Shows an enhancing soft-tissue nodule (arrow) in the

splenectomy bed, which is consistent with a splenule.


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Shows subpleural ground-glass and reticular opacities in the

lungs (arrows) with architectural distortion, findings that are

consistent with pulmonary fibrosis.


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Levofloxacin was started

2 d later, returned to hematologist-oncologist for eval of LAD

Medications- hydroxychloroquine, leflunomide, meloxicam,pantoprazole,folic acid and levofloxacin

- had never taken tumor necrosis factor antagonists

Social history- married, monogamous with wife for >10 yrs- did not smoke or drink alcohol

- worked as a painter, no recent travel

Family history- sister had had uterine cancer- no autoimmune disease or other malignancy



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PE- BP 120/60, W 68.2 kg

- Enlarged, mobile, nontender LN in bilateral cervical,

supraclavicular, axillary, and inguinal regions, L > R

- L axillary node 4 cm in diameter

Laboratory, see Table

- PT, PTT, and lupus anticoagulants normal

- Monoclonal band on SPEP, markedly elevated IgG

- Immunofixation: 2-3 ill-defined IgG bands, no light chains

One week later, a diagnostic procedure was performed



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Differential Diagnosis

Nikhil C. Munshi, M.D.

J erome Lipper Myeloma Center, DFCIBoston VA Healthcare System


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Clinical Features Important for

Differential Diagnosis Diffuse generalized lymphadenopathy developed

over a month

Lack of B symptoms History of autoimmune disease 4 years ago requiring

steroids and methotrexate

History of splenectomy

Gastro-esophageal reflux disease


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Clinical Differential Diagnosis

Non-Hodgkins Lymphoma

Follicular

Marginal Zone lymphoma (MALT) lymphoma

Aggressive Lymphoma

Lymphoplasmacytic lymphoma Non-malignant Lymphoproliferative disorder

Auto-immune disease related

Drug-induced - Leflunomide, methotrexate

Infection

Fungal, Tuberculosis, Viral

Castlemans disease


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Laboratory Features Important

for Differential Diagnosis

Normal Hemoglobin

Normal White Blood Cell Counts Negative serology for infections

Elevated b globulin and IgG

Monoclonal IgG Band


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Non-Hodgkins Lymphoma

Follicular lymphoma

++ Generalized lymph nodes, small size,

++ Normal CBC, low LDH, presence of monoclonal protein

-- Rapid growth, symptomatic disease

Marginal Zone lymphoma

++Stomach lesion, GERD, association with autoimmune disease

++Monoclonal protein, low LDH

-- Uncommon to be systemic disease, rapid growth

Aggressive lymphoma

++Generalized lymphadenopathy, Rapid growth, prior methotrexateuse and immune deficiency, Symptoms, Lymph nodes withnecrosis

-- Small size lymph nodes, LDH, Normal CBC


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Lymphoplasmacytic lymphoma (Waldenstroms Macroglobulinemia)++Generalized lymph nodes, small size, lack of symptoms,

-- Younger patient, Rapid growth

-- Normal CBC, Presence of IgG monoclonal protein

Non-malignant Lymphoproliferative disorderAutoimmune disease-related++ Active aggressive autoimmune disease, progressive increase in

immune marker (Rh factor)

-- Not usually with rapid growth, low ESR and presence ofmonoclonal protein.

Immune Deficiency-related-- Leflunomide, methotrexateuncommon cause, relation with

malignant transformation


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InfectionFugal, Tuberculosis, Viral++h/o fungal infection, generalized lymph nodes, Rapid

growth

-- relatively limited symptomsno fever

-- Normal CBC, low ESR, Presence of monoclonal IgG,negative viral serology

Castlemans disease

++ Generalized lymphadenopathy, Immune suppression

Elevated IgG-- Rapid growth, relatively asymptomatic

-- Normal hemoglobin and platelet count, low ESR,normal albumin, Presence of monoclonal IgG


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Causes of Monoclonal

Immunoglobulin

Plasma cell disorder

Chronic lymphocytic leukemia

Lymphomas of B or T cell origin

Nonlymphoid neoplasmsCML, Breast and Colon cancer

Nonneoplastic conditionsCirrhosis, sarcoidosis, parasitic diseases, Gaucherdisease, and pyoderma gangrenosum

Autoimmune conditionsRheumatoid arthritis, myasthenia gravis, and coldagglutinin disease.


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Monoclonal Immunoglobulin

Monoclonal BandIgG band without light chainMalignant and non malignant conditions associatedwith presence of monoclonal protein have either intact

immunoglobulin with both heavy and light chain, orlight chain only

Absence of light chain and presence of heavychain is observed in heavy chain disease


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Heavy Chain Disease

g Heavy Chain Disease

systemic lymphoma

a Heavy Chain Disease

Gut-associated heavy chain disease - intestinal parasites

Immunoproliferative small intestinal disease (IPSID)

Campylobacter jejuni

m Heavy Chain Diseasesystemic lymphoma with CLL like features


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Diagnosis

Gamma Heavy Chain Disease

Immunoglobulin Structure


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CDR3

NH2 NH2VH

JH

JL

L

H

CDR1

CDR2

L

H CDR1

CDR2

CDR3

C

L

CH2 CH2

CH3 CH3

D

CH1

CL

VLCH1

COOHCOOH

CH1

Antigen

Binding site

Complement

Binding site

Fc receptor

Binding site

Structure of the Immunoglobulin Molecule in Heavy-Chain Disease


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See notes

Structure of the Immunoglobulin Molecule in Heavy-Chain Disease.


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Biology of Ig in Heavy Chain

Disease In absence of associated light chain, CH1

domain of HC binds to HC-binding protein

and degradationNo secretion Light chain, if present, will bind to CH1 -

No degradation. Eventual secretion

All gamma HCD have CH1 deletedprevents degradation in absence of lightchain


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Biology of Ig in Heavy Chain

Disease

Absence of light chain

Non contiguous deletions in the V/J regionin HC

Non contiguous deletions in the switch/CH1

region in HC



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in g Heavy Chain Disease


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g Heavy Chain Disease

Diagnostic Features in This Patients

Generalized lymphadenopathy

History autoimmune disease

most frequentrheumatoid arthritis

association in 1/3 patients

M component [often


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Differences between IgG myeloma

and g HCDFeatures Myeloma g HCDLymphadenopathy - +

Hepatosplenomegaly - +Osteolytic Lesions + -

Renal involvement Commom -

SPEP/IFE Heavy and light chains Heavy chain only

Heavy chain characteristics VDJ and Truncated VDJ and

CH1-CH3 domain absent CH1


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Therapeutic considerations

Limited information and experience

Indolent diseasein some cases followed asMGUS

Treatment as lymphoplasmacytic disease CVP - CHOP Fludarabine

Rituxan

Disappearance of gamma heavy chain in responseto treatment not predictive of a good overalltherapeutic response


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Clinical Diagnosis

Ronald S. Weinger, M.D., FACP

Hematology and OncologyNorthshore Cancer Center


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Pathology

Aliyah Rahemtullah, M.D.

Hematopathology FellowMassachusetts General

Hospital


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SPEP and Immunofixation

4 days prior to evaluation

TP 7.1 g/dL (6.1-8.3)

Alb 3.8 g/dL (3.3-4.8)

Immunoglobulins (mg/dL)

IgG 2180 (694-1618)

IgA 408 (81-463)

IgM 104 (48-271)

o

Th di ti d


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The diagnostic procedure

The lymph-node architecture is effaced by a polymorphous lymphoid population with a diffusepattern of growth ( hematoxylin and eosin)


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Lymphocytes include small, mature-appearing forms, plasmacytoid lymphocytes with moderately abundant cytoplasm and

eccentric nuclei, and medium-sized cells with dispersed chromatin and slight nuclear irregularities


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CD20 mum-1


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C 0

Ki67

u

CD30


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Numerous plasma cells (arrows ) and scattered large immunoblasts are also present.

Immunohistochemical stains show that most of the lymphoid infiltrate is composed ofCD20-positive B cells, including the immunoblasts

CD1 gam


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CD1

38

lamb

da

gam

ma

kap

pa

Numerous plasma cells scattered throughout the lymph node are highlighted by the plasma-cell

marker CD138 (upper L). Immunohistochemical for heavy chains shows that the majority of

plasma cells are IgG-positive (upper R), whereas in situ hybridization for kappa (left lowert) and

lambda light chains (right lower) shows only scattered polytypic plasma cells

The total number of cells staining for kappa and lambda together appeared fewer than the numberof I G- ositive lasma cells.

Staging Bone Marrow Biopsy


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Staging Bone Marrow Biopsy

The bone marrowbiopsy specimen has an overall cellularity of 50%, which is appropriate for the

patients age, with maturing trilineage hematopoiesis (, Giemsa stain).


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Some plasma cells are mature, whereas others are atypical with open

chromatin

CD138 gamma


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lambda

g

kappa


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The plasma cells within the small clusters were positive for CD138 and IgG.

In situ hybridization for kappa and lambda light chains showed scattered

polytypic plasma cells, but the IgG-positive plasma cells within the small

aggregates were negative for both kappa and lambda light chains.(IgG

immunohistochemical stain shownabove)

SPEP d I fi ti


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SPEP and Immunofixation

at time of BM biopsy

TP 6.6 g/dL (6.1-8.3)

Alb 3.3 g/dL (3.3-4.8)

Immunoglobulins (mg/dL)

IgG 2820 (694-1618)

IgA 310 (81-463)

IgM 82 (48-271)

M component: 0.78 g/dL

o

See note

UPEP d I fi ti


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UPEP and Immunofixation

at time of BM biopsy

Total protein: 231 mg/dL

Albumin: 5.1 mg/dL

Urine IgG: ~225 mg/dL

Urinary protein electrophoresis (UPE) performed approximately 1 month later revealed

similar results , with a broad monoclonal band corresponding to IgG, without a

corresponding light chain. Calculated total urinary IgG was approximately 225 mg .


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Summary

Serum and urine studiesFree gamma heavy chains without light chain

Pathology

Cervical LN: Diffuse B-cell lymphoplasmacyticproliferation positive for gamma heavy chain;

no staining for light chains

BM biopsy: Involvement by a similar process Diagnosis

Gamma Heavy Chain Disease


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Prior Pathology

Splenectomy (14 years earlier)

400g with fibrocongestive changes

Reactive follicular hyperplasia of white pulp without morphologic

evidence of lymphoma

Bone marrow biopsy (14 years earlier)

Normocellular marrow with trilineage hematopoiesis, without

morphologic evidence of lymphoma or plasma cell neoplasm

Skin biopsy, right retroauricular area (19 months earlier)

Dermatitis with features compatible with subacute cutaneous lupus

erythematosus Findings morphologically indistinguishable from drug

hypersensitivity reaction; certain features favored this diagnosis

Cutaneous symptoms resolved with discontinuation of

methotrexate, addition of hydoxychloroquine


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Heavy Chain Diseases

Variants of B-cell lymphomas that produce abnormal

truncated heavy chains without associated light chains

Heavy chain Associated lymphoma FeaturesAlpha HCD(immunoproliferative

small intestinal disease;

IPSID)

Extranodal marginal zone

B-cell lymphoma (MALT

lymphoma) of small

intestine

Common in Mediterranean regions

Association with C. jejuni infection

May be antibiotic responsive early on

May progress to DLBCL

Mu HCD Chronic lymphocyticleukemia (CLL)

Rarest of HCDs

Vacuolated marrow plasma cells

Free urine light chains produced in

addition to abnormal serum mu chain

Gamma HCD(Franklins disease)

Lymphoplasmacytic

lymphoma (LPL)

Widespread involvement

Intermediate incidence between muand alpha HCD

Associations: systemic symptoms,

anemia, eosinophilia, autoimmune

manifestations

Fermand JP and Brouet JC, Hematol Oncol Clin North Am 1999, 13:1281Jaffe ES et al. (eds), WHO Classification of Tumours 2001


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Clinicopathologic features ofg HCD Involvement of lymph nodes,

spleen and BM most common

Several extrahematopoietic sites of

involvement have been reported

Skin or subcutaneous tissue,

thyroid, salivary glands, GI tract

(usually gastric tumor), pleura andpericardium

Skeletal involvement and renal

insufficiency uncommon

M-component on SPEP

Minority with no monoclonal band,hypo- or hypergammglobulinemia

Rare patients show no evidence of

underlying lymphoid neoplasm

Associated autoimmune disorder

present

Fermand JP et al., Medicine 1989, 68:321

Sites of disease involvementLymph nodes 54%

Spleen 56%

Liver 37%

Waldeyers ring 16%Bone marrow 59%

Extrahematopoietic sites 38%

Extent of disease involvementDisseminated lymphoproliferativedisorder 61%

Localized lymphoid proliferation 12%

Malignancy uncertain 15%

No detectable lymphoid proliferation 8%

Among 97 reported cases ofg HCD:


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Lymphoplasmacytic proliferation

Mixture of small lymphocytes, plasmacytoid lymphocytes andplasma cells (LPL-like)

Intermingled immunoblasts or large atypical, Reed-Sternberglike cells

Increased eosinophils and histiocytes, including epithelioidand multinucleated giant cells

Proliferation of small vessels

Predominantly plasmacytic proliferation

More frequently found in extranodal locations

CLL-like presentation with absolute lymphocytosis ofperipheral blood uncommon

Progression to DLBCL (usually immunoblastic variant)unusual

Fermand JP et al., Medicine 1989, 68:321Jaffe ES et al. (eds), WHO Classification of Tumours 2001

Histopathologic features ofg HCD

HCD and Autoimmunity


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g HCD and Autoimmunity

28% overall incidence of AI in patients with g HCD

Autoimmune symptoms often preceded diagnosis of lymphoidmalignancy by several years (3 years in this patient)

A minority of these patients had symptoms of AI and serumfree g heavy chains, but never developed an overt malignancy

Fermand JP et al., Medicine 1989, 68:321Wahner-Roedler DL et al., Medicine 2003, 82:236

Autoimmune Disease # casesRheumatoid arthritis 11

Autoimmune hemolytic anemia 10

Idiopathic thrombocytopenic purpura 5

Vasculitis 5

Sjogren syndrome 3

Lupus erythematosus 2

Myasthenia gravis 2

Thyroiditis 1

Total (>1 AI disease in 3 cases) 36

Autoimmune

disorders identified

in 124 reported

cases ofg HCD


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Management and Followup

Ronald S. Weinger, M.D., FACP

Hematology and OncologyNorthshore Cancer Center


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Documents

Case 13-2008-Rheum Arthritis, Lymphadenopathy