BENIGN LYMPHOID PROLIFERATIONS

Tanuja ShetProfessor and PathologistTata Memorial Hospital

Benign LymphomaPrimary disease Investigate for specific

cause

??? Neoplastic- Lymphomatoid papulosis Cutaneous lymphoid hyperplasiaEBV assoc lymphoproliferation's, PTLD

Atypical Lymphoid hyperplasia

Reactive or benign lymphadenopathy

In response to a hoard of toxic agents- MIAMI- Malignancies, infections, autoimmune, miscellaneous and iatrogenic

Persistent nodes biopsied – To rule out a lymphoma and to find a specific cause. However inspite of efforts in only 10% cases a etiologic agent can be identified

Age and site foremost in determining causes

79% of nodes <30 years are reactive Vs 39% of nodes >60 yrs

Supraclavicular node more likely to carry a specific pathology usually malignant , inguinal node which is more likely to harbor lesions due to a STD

TB in post cervical nodes, Parotid nodes in HIV

Histologic Patterns in reactive lymphadenopathy

Paracortical / T zone hyperplasia

Follicular or nodular Hyperplasia

Diffuse atypical lymphoid proliferations

Mixed patterns

Necrotizing lymphadenitisGranulomatous lymphadenitis

Sinusoidal histiocytic proliferations

FOLLICULAR OR NODULAR REACTIVE PROLIFERATIONS

Patterns of nodular reactive hyperplasiaFollicular hyperplasia Vs follicular lymphomaPTGC

Reactive follicles Neoplastic follicles Progressively transformed GC

Florid Follicular Hyperplasia –Presence of mantles, GC = CB,CC Loss of GC + Nodules of mantle cells

Follicular lymphoma –↓↓mantles, GC = >CB >CC

Reactive node Follicular lymphoma

Follicular hyperplasia Vs Follicular lymphoma

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CD20

CD3

Bcl2 staining

Bcl2 positive follicles – Follicular lymphomaBcl2 negative follicles - reactive

Progressively transformed germinal center/PTGC

Reactive pattern of unknown etiology whereby mantle cells infiltrate germinal centre forming large nodules

Affects Young males – cervical/ axillary/ inguinal nodes( Japanese patients older)

Focal (<5%) easily recognized – Florid cases mimic FL

PTGC like pattern is recognized in HIV and in pediatric marginal zone lymphoma

In one study 30% harbored a Hodgkins lymphoma-NLPHL or CHL on rebiopsy or concurrent

Hence look for RS cells within nodules

Also mimic low grade NHL

35 year old male with enlarged cervical nodes - 2.5X1.5cm

Very large nodules Mixture of mantle cells (T/B) and GC cells

No RS cells – rule out NLPHLFDC network is disrupted ( Vs NLPHL where it is expanded)

CD20

Bcl2 – does not uniformly stain – low grade NHL

CD3

Specific patterns that point etiology in a reactive Follicular Hyperplasia

Markedly thickened capsule with plasmacytosis , arteritis and phlebitis, an unusually large amount of fibrosis that penetrates between follicles – syphilis

Onion peeling or dendritic cell proliferation or FDC dysplasia in GC - Castleman's Disease

Very large follicles – HIV associated lymphadenopathy, Toxoplasma infection

Castleman’s disease Clinical manifestations of Castleman's disease (CD) are

heterogeneous

Two histologic variants : plasma cell variant and hyaline vascular disease

Two clinical variants – solitary and multicentric

Third subvariant – multicentric plasmablastic Castleman's disease with 15% POEMS (polyneuropathy, organomegaly, endocrinopathy, monoclonal proteins and skin changes)

Histologically resembles PCV, but has large plasma blasts in the mantle zone .

Castleman’s disease Hyaline vascular disease- 70%, one node enlarged to a large

size- mediastinum, cervical, axillary - intense homogeneous contrast enhancement on CT/PETCT

Plasma cell variant - <20%, single lymph node chain, frequently abdominal, majority have constitutional symptoms anaemia and ↑ESR

Multicentric CD- Generalized lymphadenopathy with splenomegaly (33–79%); hepatomegaly( 63), 15% have POEMS. HHV-8 infection seen in POEMS patients with MCD. 33–50% experience symptoms that recur and survival ranged from 14 to 30 months

Castlemans disease Etiology - HHV8 assoc with MCD - antiviral medications

result in regression of symptoms in HIV-infected patients with MCD. Other variants no conclusive evidence of viral etiology

Unicentric no mortality, death in MCD is either caused by sepsis, systemic inflammation leading to multi-organ system failure, or the development of malignancy (most commonly lymphoma).

HIV-associated CD - 23% develop Large cell lymphoma PEL like

Chemotherapy – CHOP or CVAD, Immune modulators Steroids, Interferon alpha, Thalidomide, anti IL6, Rituximab etc

24 June 2010Expanded mantle zones - lymphoid variant Lollipop follicle - vessels

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Concentric layering around GC and hyaline sclerosis

Extrafollicular Dendritic proliferation

Plasma Cell Variant of CD

HHV8LANA (brown)

Multicentric Castleman DiseaseHIV negative patients: 40-50% KSHV+, HIV positive patients: ~100% KSHV

PARA CORTICAL REACTIVE HYPERPLASIA

Markedly enlarged T zones or paracortex composed of polymorphous population of small and large lymphoid cells, immunoblasts and plasma cells and HEVDiffuse - Viral infection – EBV, HHV6, SLE, early phase of Kikuchi’s lymphadenitis

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Para cortical pattern – High proliferation - Reactive

18 yr boy with bilateral neck nodes, fever loss of weight and anorexia. FNAC NHL- 1 cycle CHOP given

EBER-In situ hybridization – Infectious mononucleosis

Sinusoidal filling of polymorphous cellsVascularity

Pattern for Nodal (tonsil) involvement in IM

Pattern I- Follicular hyperplasia with high proliferation

Pattern II- Diffuse proliferation of a heterogeneous population of cells.

→Sinusoidal filling with polymorphous cells→ Variable degree of infiltration of trabeculae/ lymph node

capsule/ perinodal fat.→ Increased vascularity. Cancer 1971,27:1029

Kikuchi like necrosis common- mistaken for autoimmune disease. Pathology Research and Practice 2004; 200:53–57

Histiocytes/ epithelioid- like toxoplasmosis Pathology Research and Practice 2010 epub

AITL like morphology in some cases - Leukemia & Lymphoma, 2010; Early Online, 1–3

Partial retainment of normal anatomy

Paracortical pattern

IM cell – Immunoblasts

Age – young patient

Think EBV/ viral reactive

Toxoplasma Lymphadenitis

Toxoplasma gondii cause of 15-20% unexplained lymphadenopathy

Most commonly affects women – post cervical nodes, occasionally generalized LN and hepatomegaly

Diagnostic triad - Sensitivity 62.5%, Specificity – 91.3%

Reactive follicular hyperplasia Patchy monocytoid B cell hyerplasiaMicrogranulomas in paracortex encroaching on

follicles

Monocytoid B cells

Loose granulomas

Necrotizing lymphadenopathy

•Kikuchis like lymphadenitis•Similar lesions with HHV6/HSV6/CMV SLE

Tuberculous lymphadenitis – Typical and atypical

Necrosis with granulomas

Necrotizing inflammation without granulomas

Non tuberculous –Pallisaded granulomasCat scratch disease,LGV,Tularemia Atypical mycobacteria

> Typical TB

Nodal infarct

Infarcted Lymphoma Vs Idiopathic

Kikuchi’s lymphadenitis(KFD) Idiopathic, self-limited necrotizing lymphadenitis , more

common in Asia than North America , described in Japan in 1972

Age group 25 (1-64) and 70% was younger than 30. Clin Rheumatol. 2007 Jan;26(1):50-4

Symptoms - lymphadenomegaly (100%), erythematous rashes (10%), arthritis (5%), hepatosplenomegaly (3%), leucopenia (43%), high erythrocyte sedimentation rate (40%), and anemia (23%) being the most common findings.

Self-limiting condition, usually resolving within 4 months

Etiology

KFD was associated with SLE (32 cases), non-infectious inflammatory diseases (24 cases), viral infections (17 cases) - HHV6, EBV in children J Pediatr Hematol Oncol. 2001 May;23(4):240-3 Mod Pathol. 2004 Nov;17(11):1427-33

120/471 had positive serology for HHV6/ HSV6 South Med J. 2003

Mar;96(3):226-33

The disease was self-limiting in 156 (64%) and corticosteroid treatment was necessary in 16 (16%) of the cases.3-4% recur, Rare fatal cases - heart failure with necrotizing foci with a dilated heart and due to hemophagocytic syndrome. Arch Pathol Lab Med. 2010;134:289–293

Para cortical pattern – Aopototic cells= cellular phase of Kikuchis lymphadenitis

Three phases proliferative, necrotizing, and xanthomatous

Well defined Zones , Crescentric histiocytes, Plasmacytoid dendritic cells border necrosis

Xanthomatous Phase of Kikuchis lymphadenitis

The histiocytes of KFD characteristically express myeloperoxidase in addition to lysozyme, CD68 and CD4Lymphocytes are predominantly CD8 T cells, in contrast to mainly CD4 T cells in other types of lymphadenopathy with T-zone expansion

TB Vs Kikuchi like lymphadenitis

Presence of granulomas Haphazard necrosis, Presence of neutrophils and fibrosis

GRANULOMATOUS LESIONS IN NODES

TB or not TBTB Vs sarcoidosisTB Vs atypical mycobacterium infection

Problems in tuberculosis lymphadenitis

Granulomas with many etiologic agents

Disease = Infection + Immunity – modified

Recognition = Definitive therapy distinct from any bacteria

Confirmation of TB Staining for acid-fast bacilli has low sensitivity, as its detection limit is

>104 bacilli per slide, or 104 bacilli per ml of specimen - tuberculous lymphadenitis are paucibacillary

PCR has been shown to have sensitivity ranging from 75 to 100% and specificity of 99 to 100% - but false positives known

Culture is the gold standard – but long duration

Immunohistochemistry with anti-MPT64 antiserum Modern Pathology (2006) 19,1606–1614

Tuberculosis Vs sarcoidosis

Caseating granulomas

Early granulomas carry a lymphoid cuff

Irregular in every way Tissue destruction with

fibrosis

Non caseating granulomas

Naked granulomas Sharply defined

granulomas with concentric whorls of epithelioid cells

Fibrosis and increased reticulin

Asteroid bodies/ Shaumann/ H W bodies

Tuberculosis Sarcoidosis

Reticulin poor granulomas Reticulin rich granulomas

Inclusions in giant cells in a granuloma – not very specific

Asteroid body – halo with radiating spikes, also seen in fibrin rich exudates

Schaumann (Conchoidal) bodies – cell death with lamellated calcium oxalate deposition

Hamazaki Wesenberg bodies –Lysosomal bodies with lipofuscinpigment usually extra cellular but occasionally in giant cells – satin with AFB and Silver stains

40 yr old already taken AKT for cervical and mediastinal nodes ??? sarcoidosis

Diagnosis-???

Tuberculosis- MDR – Improvement after second line

TYPICAL OR ATYPICAL MYCOBACTERIA – DIFFERENT THERAPY AND CLINICAL PROGRESS

Difficult on histopathology aloneDifficult without culture studiesPathologist should know when to suspect and mention a possibility of atypical mycobacterium

Atypical Mycobacterial Infections

M. kansasii and M. avium-intracellulare account for most of the human mycobacterial disease

Mycobacterium avium intracellulare frequently affects AIDS patients.

Mycobacterium marinum and M. ulcerans cause skin infections/ swimming pool granuloma.

M. avium-intracellulare and M. kansasii cause lung disease.

M. scrofulaceum is a common cause of painless cervical lymphadenitis in children anterior superior cervical chain or submandibular area

1) Eosinophilic granular non coagulative necrosis distant granulomas

Typical mycobacteria Atypical mycobacteria - MAI

40X 40X

100X 100X

2)Size, Non beaded, Plenty

Mycobacterium Avium Intracellulare Infection

3)Sheets of histiocytes forming pseudoumor

GRANULOMAS – SPECIFIC ETIOLOGIC AGENTS

Histiocytic clusters only – Leprosy / LeishmaniaPallisaded necrosis – Cat scratch disease, LGV, TularemiaNon necrotic granulomas with eosinophils –Parasites – Filariasis/ Strongyloides Foreign body granulomas with suppuration (+/-epithelioid cells)- fungus

Filarial Lymphadenitis – Prominent eosinophils within granulomas, lymphatic sclerosis/ fibrosis

50 year old lady with multiple lesions in brain, generalized lymphadenopathy

Disseminated mucormycosis

Necrotizing Pallisaded granulomas – Cat scratch, LGV, TB

Warthin Starry Stain – Bartonella Species-Bacillary angiomatosis/ Cat scratch disease (web page atlas)

45 year old male with cervical nodes

GMS - diagnosis

Lepromatous leprosy in nodes

Always do PAS /GMS/AFB in all non TB granulomas or necrotizing processes in nodes

MIXED PATTERN

Commonly associated immunodeficiency and drug induced

HIV associated Lymphadenopathy

HIV virus has strong tropism for lymphoid tissue, Dendritic cells and CD4 cells

Follicular dendritic cells entrap HIV to present it to the T cells hence initially stimulation of GC = pattern A. Subsequent proliferation of virus leads to depletion of dendritic cells and loss of GC = follicular lysis and finally involution of lymph nodes( pattern C)

Florid Follicular Hyperplasia – Large follicles

Bcl2

CD20

Warthin Finkeldey cells

Para cortical hyperplasia with follicular lysis

Pattern C

Mixed pattern – variable – Drug Induced changes – Paracortical proliferation, Vascular changes and dendritic changes are seen

SINUSOIDAL PATTERN

68S -100

Phagocytosis in absence of necrosis rule out SHML

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Rosai Dorfman disease/ SHML Described by Destombes in 1965- Rosai Dorfman SHML usually presents with massive cervical

lymphadenopathy, rarely extra nodal manifestations( RDD for extranodal forms)

43% have extranodal involvement, SHML registry H & N - 87% cervical nodes, 16% nasal/PNS, ocular – 11%, salivary gland 7%, oral – 4%, tonsil- 1%

Commonly seen in adolescents and young adults, African and Caribbean population > Asians

The disease is self-limiting with 70–80% undergoing spontaneous remission, Steroid therapy, sometimes chronic with a relapsing and remitting pattern ( CT/ RT).

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SHML - Etiology Reactive because the histiocytic proliferation is polyclonal & is

thought to be secondary to abnormal cytokine production

? Immunologic abnormality – poor outcome - elevated erythrocyte sedimentation rate, autoimmune hemolytic anemia, Polyarthralgia, rheumatoid arthritis, glomerular nephritis( ALPS) etc

? Infective etiology - Antibodies to EBV and human herpes virus (HHV)-6 have been reported

IHC- S-100 +, CD 163+, Lysozyme, pan macrophage antigen +( CD68, HAM 56, CD14, CD64, CD15)

Death due to immune dysfunction, hematologic antibodies, Wiskott Aldrich syndrome

“ATYPICAL LYMPHOID PROLIFERATION OR HYPERPLASIA.” 35% OF REBIOPSY HAVE A LYMPHOMA

Lymph nodes with distorted or effaced architecture, that falls short of the criteria for malignancy

Usually Benign outcome

Correlation of immunohistologic, karyotypic, virologic,and genotypic analyses with the clinical findings, previous medications, and family history

Causes of Diffuse Atypical Lymphoid proliferations

Autoimmune diseases or Immunodeficiency syndromes

Chronic viral illnesses - Epstein Barr virus, Chronic HTLVIII, B19 etc

HIV infection without immunodeficiency

Drug induced lymphadenopathy –carbamazapine, dilantin induced

EBV infection in patients on immunosuppressive therapy-Antithymocyte globulin , Azathioprine, Corticosteroids , Cyclosporin, Tacrolimus, Methotrexate

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27 yr old male with massive cervical nodes, Labeled as CHL/ALL. Off and on lymph nodes and peripheral blood lymphocytosis since childhood

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CD 3 CD8 = CD4 Tdt negative

Summary Paracortical pattern – reactive – high

proliferation not Hodgkins Coagulative necrosis – TB Non coagulative necrosis, no polymorphs –

Kikuchis Destructive granulomas – TB > sarcoidosis GMS and AFB in all necrotizing granulomas Atypical lymphoid proliferation- essential to

have clinical details

24 June 2010