Lymph Nodes

Reactive Nonspecific Changes

Immunodeficiency-Associated Lymphoproliferations

Reactive Follicular Hyperplasia (RFH)

Reactive Paracortical Hyperplasia (RPH)

Infectious Causes of Lymphadenitis

Overview of Immunodeficiency-Associated Lymphoproliferative Disorders

Autoimmune Lymphoproliferative Syndrome

Immunomodulating Agent-Associated Lymphoproliferative Disorder

Posttransplant Lymphoproliferative Disorder, Early Lesions and Polymorphic

Posttransplant Lymphoproliferative Disorder, Monomorphic

Chronic Granulomatous Lymphadenitis

Suppurative Lymphadenitis

Mycobacterium tuberculosis Lymphadenitis

Atypical Mycobacterial Lymphadenitis

Mycobacterial Spindle Cell Pseudotumor

Cat-Scratch Disease

Bacillary Angiomatosis

Lymphogranuloma Venereum Lymphadenitis

Whipple Disease

Syphalitic Lymphadenitis

EBV+ B-cell Lymphoproliferative Disorders

  • Infectious Mononucleosis

Histoplasma Lymphadenitis

Cryptococcus Lymphadenitis

Toxoplasma Lymphadenitis

Coccidioides Lymphadenitis

Herpes Simplex Lymphadenitis

Cytomegalovirus Lymphadenitis

Human Immunodeficiency Virus Lymphadenitis

Nonhematopoietic Proliferations in Lymph Node

Epithelial Inclusions in Lymph Node

Nevus Cell Inclusions in Lymph Node

Vascular Transformation of Lymph Node Sinuses

Angiomyamatous Hamartoma

Palisaded Myofibroblastoma

Metastatic Kaposi Sarcoma

Reactive Lymphadenopathies

Spleen

Inflammatory Pseudotumor of Lymph Node

Progressive Transformation of Germinal Centers (PTGC)

Kikuchi-Fujimoto Disease

Rosai-Dorfman Disease

Kimura Disease

Unicentric Hyaline Vascular Variant Castleman Disease

Multicentric Castleman Disease

Rheumatoid Arthritis-Related Lymphadenopathy

Sarcoid Lymphadenopathy

Dermatopathic Lymphadenopathy

Hemophagocytic Lymphohistiocytosis

Lymphadenopathy Associated with Joint Protheses

Lipid-Associated Lymphadenopathy

Lymphadenopathy Secondary to Drug-Induced Hypersensitivity Syndrome

IgG4-Related Disease

Embryology, Anatomy and Histology

Splenic hamartoma

Cord capillary hemangioma

Sclerosing nodular angiomatoid transformation (SANT)

Littoral cell angioma

Splenic Marginal Zone Lymphoma (SMZL)

Splenic Diffuse Red Pulp Small B-cell Lymphoma

Diffuse Large B-cell Lymphoma (DLBCL) Arising in the spleen

Myeloid neoplasms

Lymph Nodes

Note: Primary lymphoid organs = BM and thymus

- site of lymphocyte birth and maturation by a process that does not involve antigens; have no follicles and make mature naive lymphocytes

 

Secondary lymphoid organ (LNs, spleen, MALT) activate naive lymphocytes with antigen and have follicles

 

Embryology

 

Content body

 

Anatomy, Histology

 

Lymph nodes are secondary lymphoid organs (they activate mature naive lymphocytes with antigen and have follicles)

- contain lots of afferent but few efferent lymphatics

 

Cortex is right under the capsule and has follicles with B cells; outer cortex has B cells and inner (deep) cortex has CD4+ T cells

- primary follicles are dense and dormant (lacks mantle and germinal center)

- secondary follicles pale and active c germinal center (where activated B cells proliferate after T cell activation) and mantle (with follicular dendritic cells [FDCs] that interact c mature B cells)

 

Germinal centers in secondary follicles are normally polarized c a dark centroblast region c blast-like B cells and a centrocyte region that is lighter c B cells c irregular nuclear contours and cleaved nuclei

- centroblasts and centrocytes both express CD10

 

Medulla = medullary cords (plasma cells and lymphocytes) and medullary sinuses (macrophages + reticular cells; communicates c efferent lymphatics)

- near the hilum; has lots of BVs and lymph sinuses

 

Paracortex bwt outer cortex and inner medulla has (CD4+) T cells (after undergoing differentiation in thymic cortex and medulla) and interdigitating cells (IDCs; express CD1a and S-100; antigen-presenting cells that help initiate immune response)

- has high endothelial (post-capillary) venules, where lymphs enter LN  from blood

- atrophy of paracortex in DiGeorge syndrome bc do not have T cells

 

***T cells found in structures that begin with "P" = PALS in spleen and Paracortex of LNs; B cells found in follicles - follicles of cortex in LNs and follicles of white pulp in spleen***

 

[3]

 

Reactive Nonspecific Changes

 

Germinal Center polarization

- has dark zone (centroblasts) and light zone (centrocytes)

 

Cortex with B-cells, primary and secondary follicles

Paracortex c T-cells, blood vessels, interfollicular zone

Medullary cords have plasma cells and T cells

Sinuses c monocytes

 

B-cells in follicles and sprinkled in interfollicular region

(+) parafollcular immunoblasts

Mostly positive in T-cells in paracortex

CD4:CD8 ratio usually 3-4:1

 

Reactive Follicular Hyperplasia (RFH)

 

B9, Nonspecific, Hyperplastic follicles w secondary germinal centers

- clinically is a big LN, may be assoc c fever, fatigue

- pt age and evolution of dz important, as w size and location

Causes include medications, bacteria, viruses (EBV, HIV), autoimmune dz, Castleman dz, progressively transformed GCs, HIV-assoc lymphadenopathy, Rheumatoid lymphadenopathy (polytypic plasma cells and neuts in sinuses), and Syphilitic lymphadenopathy (thick capsule c plasma cells), usually cannot identify etiology

 

Location may suggest underlying dz

- cervical --> infectious mononucleosis

- posterior cervical --> Toxoplasmosis

- Parotid, submaxillary, epitrochlear --> HIV infx

- Cervical and axillary --> Cat-scratch dz

- Inguinal --> STD

- Supraclavicular --> Malignancy, esp in older pts

 

Gross: Generally, LNs >1 cm are abnormal

- inguinal LNs should be < 1.5 cm, epitrochlear <0,5 c

 

Micro: many large follicles, variety of size / shape

- have central germinal center (GC) and well-demarcated mantle zone

- occasional coalescence of follicles ok

- in spleen, reactive follicles are in the white pulp, in LN they are usually around the cortex, not medulla

 

Germinal center (GC): centroblasts and centrocytes, few T-cell, scattered histiocytes

- usually are polarized (have light and dark zones)

-- dark zone: many centroblasts (with high N:C ratio) and mits

-- light zone: predominantly centrocytes and follicular dendritic cells

 

Centroblasts: 3-4x size of small lymphs; have 1-3 nucleoli

 

Mantle zone: concentric layers of small naive (non-antigen exposed) B-cells

- proliferate to become centroblasts when exposed to antigen

 

IHC: GC and mantle zone express polytypic Igs and pan-B-markers

- centroblats and centrocytes CD10+, BCL6+, BCL2-

- T-follicular helper cells (Tfh) CD4+, CD10+, Bcl-6+, CXCL13+, PD1/CD279+

- Follicular dendritic cells (have 2 square-shaped adjacent nuclei) CD21+, CD23+, CD35+

- Histiocytes: CD68+, CD163+

 

May be associated with an EBV+ Lymphoproliferative disorder (EBV+ LPD)

- tend to occur early after transplantation

- overall architecture preserved with minimal interfolllicualr expansion

- Distribution of EBER+ cells often confined to a few follicles

- EBV+ T-cell hyperplasias also exist

- Dasatinib-related hyperplasia is another thing

 

Lymphoid "trafficking" can be seen in conditions with increased circuliating lymphocyts, eg viral, activated lymphcytes, immunoblasts also present

- if cytologically atypical, leukemia / lymphoma should be considered

 

Genes: Polyclonal IGH rearrangements

- No evidence of t(14;18) or IGH-BCL2 fusion sequences

 

DDx: Follicular lymphoma (FL), has polymorphic cells, inc mits (dec in FL), normal macrophages (dec in FL), neg Bcl-2 and t(14;18) (pos in FL), preserved architecture, GC morphologic variation, and no back to back follicules (back to back in FL)

- Atypical follicular hyperplasia - term for follicular lesions with some features suggestive of FL, now an uncommon diagnosis

- PTGC - usually assoc c RFH, PTGC has larger follicules than RFH, reactive centrocytes and centroblasts are BCL6+ and BCL2-, small round lymphocytes are BCL6- and BCL2+

- NLPHL - nodules are much larger than follicles, predominance of small lymphs (mostly reactive B-cells); LP cells are CD20+, CD45+, BCL2-; CD57 cells are increased in nodules and can form rosettes around LP cells

- LRCHL, nodular variant - nodular variant can closely resemble NLPHL, , neoplastic cells are CD15+, CD30+, CD20-/+, PAX5+, CD45-

- autoimmune or connective tissue disease (rheumatoid arthritis, Sjogrens)

- other infectious lymphadenitis (Toxoplasma gondii, syphilis, early viral [EBV or CMV])

- Castleman's disease

- May be nonspecific

Reactive follicle - mantle zone is more attenuated near area of dark zone because that is where the naive B-cells have been recruited to become centroblasts in the dark zone. As the centroblasts undergo somatic hypermutation to match with antigen they mature into centrocytes (although many centroblasts undergo apoptosis); other cells include follicular dendritic cells (involved with antigen presentation) and tingible body macrophages (histiocytes; have variable apoptotic debris in them)

PD1 expression in RFH in a teenager with drug hypersensitivity. Stronger staining in reactive residual germinal center and weaker and more variable staining in reactive paracortical T-cells

Reactive Paracortical Hyperplasia

 

Expansion of paracortex from T-cells proliferation, which can be due to drugs, viruses and vaccines

- architecture is preserved

- Immunoblasts in a sea of small T cells and histiocytes (immunoblasts can be CD30+, but this is not Hodgkins!!)

- assoc c viral infx, post-vaccine lymphadenitis, Infectious mononucleosis (EBV), drug-induced hypersensitivity, dermatopathic lymphadenitis, histiocytic necrotizing lymphadenitis, SLE

 

Micro: T-cells appear monomorphous, small and mature appearing

- have almost evenly-spaced scattered interdigitating dendritic cells sprinkled throughout that gives it a mottled-effect

 

Reactive paracortical and reactive follicular hyperplasia tend to co-exist

 

DDx: may be nonspecific

- dermatopathic lymphadenitis

- viral lymphadenitis (CMV, HSV, EBV)

- drug-induced (phenytoin)

- Kikuchi-Fujimoto

- may be associated with a varying degree of an immunoblastic reaction

- Peripheral T-cell lypmhoma (PTCL) - some PTCL aberrantly express CD20, rarely CD79a, CD15, the may have aberrant subset antigens (double loss of CD4 and CD8, or double expression of CD4 and CD8), and antigen loss (CD7 not specific, CD5 negative in gamma delta, other PTCL)

 

Reactive paracortical hyperplasia [3]. Hyperplasia of the paracortex outside of follicles. Can have vaguely nodular areas of enlargement of the paracortex. The T-cells appear monomorphous, small and mature appearing. Have almost evenly-spaced scattered interdigitating dendritic cells sprinkled throughout that gives it a mottled-effect

 

Sinus Pattern

 

Includes sinus histiocytosis, Langerhans cell histiocytosis, Rosai-Dorfman dz, Hemophagocytic syndrome, and vascularization of sinuses

Crystal-storing histiocytosis, filled with kappa light chain from plasma cells here [7]

Lymph node nevus

 

Positive for HMB45, but cells are not atypical

Nodal nevus

Vascular Changes in lymph nodes

 

 

Prominent hilar vessels

- "Vascular transformation of the sinuses" - usually assocaited with blockage of efferent lymphatics (or veins) resulting in proliferation of hilar vessels

 

Plump high-endothelial venules

- Angioimmunoblastic T-cell lymphoma

 

Increased vascular elements

- Angioimmunoblastic T-cell lymphoma

- Bacillary angiomatosis

- Less commonly B-cell lymphoma

 

Vascular hyalinization

- inflammatory conditions

- hyaline-vascular Castleman disease

 

Vascular neoplasms

- hemangioma

- angiomyolipoma

- Kaposi sarcoma

Monocytoid B-cells

 

Reactive conditions

- Viral lymphadenitis

-- EBV, CMV, HIV / AIDS

- Toxoplasma lymphadenitis

 

Malignancy

- Marginal zone lymphoma

- Lymphoplasmacytic lymphoma (LPL)

- Mimicking monocytoid B-cells: certain T-cell lymphomas (AITL)

Monocytoid B-cells

Infectious Causes of Lymphadenitis

Chronic Granulomatous Lymphadenitis

 

-

Suppurative Lymphadenitis

 

-

Mycobacterium tuberculosis Lymphadenitis

 

-

Atypical Mycobacterial Lymphadenitis

 

-

Mycobacterial Spindle Cell Pseudotumor

 

-

 

Cat-scratch disease

 

Caused by Bartonella henselae; involves skin (red papule that can become encrusted) and Cervical and axillary LNs

- LNs have different micro characteristics depending on time frame

 

Dx: can confirm c serology

 

Micro: stellate necrotizing granulomas, neuts and B-cell hyperplasia

- clumps of bacili with Warthin-Starry or Hopps stain  in walls of capillaries, in macrophages lining sinuses or near germinal centers and in areas of necrosis

- can also ID the bugs c PCR

 

Early - follicular hyperplasia and lots of histiocytes

Intermediate - granulomatous changes

Late - abscesses of various sizes c stellate necrosis and neutros surrounded by pallisading histiocytes

- sinuses filled c monocytoid B cells (unlike toxoplasmosis, peri-/intrafollicular epithelioid cells are absent)

 

DDx:

 

Px: self-limiting; resolves spontaneously

 

 

Cat-scratch disease

Bacillary Angiomatosis

 

-

Lymphogranuloma Venereum Lymphadenitis

 

-

Whipple Disease

 

-

Syphalitic (luetic) Lymphadenitis

 

Infection with Treponema pallidum

- can involve a variety of sites, such as lip, mouth, soft palate, tongue, rectum, anus

- usually has a prominent plasma cell infiltrate, but can have just lymphocytes or eosinophils

- shows both follicular and paracortical hyperplasia

 

Stage of infection corresponds to predominant histiology

- Primary: acute necrotizing lymphadenitis / chancre (rarely seen)

- Secondary: follicular hyperplasia with plasmacytosis, granulomas, perilymphadenitis (most commonly seen)

- Tertiary: necrotizing granulomatous lymphadenitis / gumma (rarely seen)

 

Lymphadenitis usually regional to the chancre

- typically inguinal, but could involve cervical nodes if infection via oral route

 

Exposure to sexually transmitted infection often not known or elicited

 

On physical exam, chancre may be misdiagnosed as another type of ulcer, related to cancer or other infection (HSV)

 

Micro: Follicular hyperplasia with inter- and intrafollicular plasmacytosis

- capsular and trabecular fibrosis with lymphoplasmacytic infiltrate

- paracortical expansion by clusters of epithelioid histiocytes (+/- suppurative features)

- endarteritis or venulitis may be present

 

IHC: anti-Treponema IHC can react with other spirochetes and requires serologic confirmation

 

DDx: immune disorders with plasmacytosis

- lymph nodes: RA, IgG4-related disease, Castleman disease --> although all of these diseases lack granulomatous component with associated neutrophils

- Extranodal sites: B-cell lymphoma with plasmacytic differentiation (eg MALToma) or carcinoma -- unusual pattern of inflammation, resolve with immunohistochemistry

EBV+ Lymphoproliferative Disorders

 

Ebstein-Barr Virus (HHV-4)

- double-stranded DNA virus isolated from Burkitt lymphoma cells

- EBV established lytic and latency programs in host cells

- EBV-infected B-cells persist within the memory of B-cell pool of most immunocompetent hosts

- EBV-encoded latent genes induce B-cell transformation by altering gene transcription and activting signaling pathways

- Immunosuppressed patients are at increased risk of developing EBV-associated B-cell lymphoproliferative disorders [8]

 

EBV+ Lymphoproliferative Disorders

- Spectrum from self-limiting hyperplasias to aggressive lymphomas

- Most often occur in immunodeficient patients; PTLD is the best studied

- Spectrum less well understood in T and NK cell proliferations

- Treatment options must be adapted to the immunodefiency context with an incremental approach to clinical management [8]

 

EBV+ B-cell Hyperplasias

WHO 2008: "Early Lesion", WHO 2016: "Non-destructive lesion"

- Mass-forming lesions with preservation of tissue architecture

- Clinical context is important to separate EBV+ hyperplasia from other non-specific causes of hyperplasia

- Polytypic kappa and lambda expression

- Occasional clonal IG or simple karyotypes present; although not indicative of malignancy, may lead to overdiagnosis as lymphoma

- Most hyperplasias regress spontaneously

- Rare concurrent or subsequent EBV+ B-LPD may occur; at least a subset are clonally related

 

Three kinds of EBV+ B-cell hyperplasias:

1. IM-like hyperplasia

2. Follicular hyperplasia

3. Plasmacytic hyperplasia

Infectious mono can look like DLBCL

http://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(09)70351-1/fulltext

Infectious Mononucleosis (IM)

 

Paracortical hyperplasia, paracortex with moth-eaten appearance and has lots of lymphs which can be small to large sized, as well as immunoblasts, histiocytes and plasma cells

- usually self-limited, and in cervical lymph nodes
- peripheral blood has atypical lymphocytosis (Downy cells) which are CD8+ T cells

 

Early: Reactive follicular and monocytoid B-cell (MBC) hyperplasia

- monocytoid B-cell (MBC) hyperplasia seen in early CMV or EBV infection, Toxoplasma, HIV-associated LAD, or non-specific benign hyperplasia

- MBCs are typically negative for BCL2, whereas they are positive in marginal zone lymphoma

- DDx: marginal zone lymphoma -- has more extensive proliferation with confluence and architectural effacement, absence of other reactive patterns of lymphoid hyperplasia, is positive for BCL2 by IHC  (benign monocytoid B-cells are negative for BCL2) and is monoclonal (by flow, IHC, or ISH)

 

Late: prominent paracortical hyperplasia with numerous scattered immunoblasts and hypervascularity

-- DDx: CHL, large cell lymphoma

 

Micro:

- expanded paracortical area

- sheets and clusters of immunoblasts may mimic DLBCL

-- these immunoblasts are CD30+, CD15-, ALK1 neg, EMA neg, CD45+ and EBV+, and some are T-cells (PAX5+) and some are T-cells (CD3+)

 

 

Labs: positive monospot / heterophile antibody, acute infection has serologies consistent with recent infeciton (EBV IgM and IgG)

- RT-PCR shows a high viral load (a positive viral load in the setting of negative serologies = acute infection), although patients with EBV-associated lymphomas will also have a high viral load

- peripheral blood with atypical lymphocytes, which are actually T-cells reacting to infected B-cells and can show an inverted CD4:CD8 ratio by flow cytometry

- remote infx has IgG EBNA and IgG VCA

- gene rearrangement studies: (Oligo)clonal pattern for T-cell receptor may be present

 

IHC:

Immunoblast phenotype: CD20+ B-cells co-expressing CD30 and MUM1, negative for CD15, EBV-EBER positive (predominantly in interfollicular areas, 10-70% of cells, median 30%) [3]

- absence of BCL6 on the large cells that are positive for MUM1 should be a good clue

- helpful / reassuring features: polyclonal Kappa / Lambda expression by IHC

- retention of OCT2 and BOB.1

- inverted CD4:CD8 ratio in the background of T-cells

 

DDx: DLBCL - a clue to help distinguish benign infectious mono from DLBCL is that in the benign cases of mono there may be areas with mixed inflammation in the background

Case of infectious mononucleosis of the tonsil with necrosis and ulceration of the epithelium, with a RS-like cell that appears similar to CHL, with CD30+ cells, although the CD30+ cells are of varying size and shape, which is different from CHL, the EBER-ISH highlights the RS-like cells, but there is a greater variability in the shpe of the RS-like cells

Histoplasma Lymphadenitis

 

-

Cryptococcus Lymphadenitis

 

-

 

Toxoplasma Lympadenitis

 

Infection with Toxoplasma gondii. One of the MC parasitic dz's of humans; typically in the posterior cervical LNs of young women, which are firm and moderately enlarged

- lymphadenopathy occurs in the late stages of acute infection

- most cases subclinical and do not require tx

 

Micro: the triad -

1) reactive follicular hyperplasia c lots o mits and phagocytosis of nuclear debris;

2) small granulomas made of pink epithelioid histiocytes in the paracortex that encroach and involve the GCs

- should NOT have well-formed granulomas (which you may see with sarcoidosis), multinucleated giant cells, or necrosis

3) distention of sinuses by monocytoid B cells

- not common to see find T gondii organisms

 

Dx: should confirm suspicion c Sabin-Feldman dye test, toxoplasma IHC, or IgG immunofluorescence ab test PCR

 

Coccidioides Lymphadenitis

 

-

Herpes Simplex Lymphadenitis

 

-

Cytomegalovirus (CMV) Lymphadenitis

 

- Cytomegaly with viral inclusions, which can be seen in moncytoid B-cells (MBCs) in immunocompetent, in paracortex in immunocompromised, and are generally seen in endothelial cells, sometimes T cells or M0 cells

 

HIV-related lymphadenopathy

 

May be confused with follicular lymphoma

- with lymphocyte depletion, have dec follicular size

 

Some say that the follicles here look like continents or animal crackers

 

3 flavors:

1) Follicular hyperplasia - irregular GC, naked GC, follicle lysis, monocytoid B-cells

 

2) Follicular involution - regressed GC, thin mantle zone, histiocytes, immunoblasts

 

3) Lymphocyte depletion - small LN, no follicles, histiocytes, erythrophagocytosis

 



HIV related lymphadenopathy with follicular hyperplasia showing large irregular germinal centers surrounded by inc clear monocytes

HIV related lymphadenopathy, follicular involution

Florid follicular hyperplasia in HIV, looks like animal crackers [7]

Reactive Lymphadenopathies

Inflammatory Pseudotumor of Lymph Node

 

-

 

Progressive Transformation of Germinal Centers (PTGC)

 

B9 reactive condition that causes partial effacement of LN architecture; usually young adults, unknown etiology, M>F

- cervical LN in 50%

- assoc c reactive follicular hyperplasia

- mantle zone lymphs migrate to and disrupt germinal centers (GCs) in multiple areas of the nodules

- no monotypic B-cell population

 

Micro: large follicles 3-5x the normal size of adjacent reactive follicles, show hyperplastic germinal centers

- interfollicular region typically uninvolved

 

IHC: GCs CD10+, BCL6+, BCL2-; mantle zones IgD+, BCL2+, CD10-, BCL6-

 

DDx: NLPHL, LRCHL nodular variant, FL floral variant, HIV-assoc lymphadenopathy, reactive follicular hyperplasia

 

Px: usually resolves spontaneously

- although related to Nodular Lymphocyte Predominant Hodgkin Lymphoma (NLPHL), no data supports transformation of PTGC to NLPHL

 

 

Kikuchi-Fujimoto disease

 

Kikuchi-Fujimoto disease (KFD)

 

- aka Histiocytic Necrotizing Lymphadenitis

 

First described in young women in Japan/Asia, but affects all ages and sexes; presents as persistent painless cervical lymphadenopathy c fever

- usually b9 and self-limited; no known etiology (possibly viral); important to r/o malignancy

- dx can be made on FNA showing plasmacytoid dendritic cells

- lab tests for organisms neg

- can look similar to SLE

 

3 phases

1) Proliferative - Crescentic histiocytes (+CD68), plasmacytoid denditic cells (+ CD123/303, TCL-1), mostly CD8 T cells, no plasma cells, not simialr to SLE

- reactive follicular hyperplasia (RFH) predominates in early lesions with patchy paracortical expansion

- immunoblasts more apparent (can be sheet-like, as seen in EBV infection), single cell necrosis with some karyorrhectic debris typically present

-- DDx: large cell lymphoma, immunoblasts in Kikuchi can be T-cells, which can raise the possibility of a peripheral T-cell lymphoma (PTCL)

 

2) Necrotizing - more mature nodules with focal to extensive areas of frank geographic necrosis, homogenous eosinophilic appearance with abundant karyorrhectic debris

- has necrosis c marked apoptosis

- acute inflam absent

 

3) Xanthomatous - resolution phase with numerous foamy macrophages

 

Micro: - nodules contain variable mixture of immunoblasts and histiocytes and plasmacytoid dendritic cells; few plasma cells, neutrophils consicuously absent

- lots of necrotic debris, scattered fibrin deposits, and mononuclear cells trying to clean it up

 

Plasmacytoid dentritic cells and activated T cells are numerous (though plasma cells and neutros are few)

- useful feature is the lack of neutrophils, plasma cells, and eos

 

Plasmacytoid dendritic cells are IFNa-producing cells with role in antiviral immunity

- resemble plasma cells, dispersed (not condensed) nuclear, chromatin

- Frequently observed in KFD (cluster at edge of nodules), viral infections, Castleman's disease

 

IHC: highlights predominance of CD3 cells and macrophages

- Plasmacytoid dendritic cells -- medium-sized with monotonous, round to oval nuclei, and basophilic cytoplasm, CD2+, CD4+, CD43+, CD123+, CD68+ (weak), CD3-

- Immunoblasts -- large with vesicular round nuclei and prominent nucleoli - CD3+, CD8+ > CD4+, many TIA+, granzyme+

- Histiocytes -- medium-sized with oval or crescent-shaped nuclei, foamy of debris-laden cytoplasm, are CD68+ (strong), MPO+, lysozyme+

 

Px: excellent -- resolves spontaneously

 

DDx: Peripheral T-cell Lymphoma NOS -- PTCL has completely effaced architecture, monomorphous, lack of characteristic admixture of cell types including crescentic / foamy histiocytes and PDCs

- Nodal PTCL-NOS usually CD4+ vs CD8+ immunoblasts in KFD

- Beware of diagnosing PTCL-NOS in a child or young adult --> exceedingly rare in this age group!!!

 

MBCs tend to be more irregular in shape, have mature mature rather than dispersed chromatin, somewhat more abundant cytoplasm, and have a sprinkling of neutrophils

 

Rosai-Dorfman disease (RDD)

 

- aka sinus histiocytosis with massive bilateral  lymphadenopathy (SHML)

 

Massive painless bilateral LN enlargment in neck of teenager c fever, leukocytosis, inc ESR, and polyclonal inc IgG usually in black kids/teens (though can occur at any age)

- traditionally considered reactive, non-neoplastic proliferation of unusual subset of macrophages

- etiology unknown, but infectious origin suggested

 

Rare; children/young adults (mean 20 yrs).

•More common in males of African descent.

•Bilateral painless massive cervical LAD; fever, weight loss.

•mediastinal, inguinal, retroperitoneal LN may also be involvement.

•Extranodal involvement in ~40% of cases [skin, nasal cavity, soft tissue, orbit, bone (lytic lesions), salivary gland, CNS, breast, pancreas].

- anemia with lymphopenia may be seen at diagnosis

- has characteristic cytologic features with striking emperipolesis

__________________________________________

Gross: nodes bound together by fibrosis c gray to yellow cut surface

__________________________________________

Micro: dilated sinuses c lymphs, plasma cells, and foamy histiocytoid cells c vesicular nuclei and lots of pale cytoplasm

- histiocytes have emperipolesis / lymphocytophagocytosis (they ate some lymphs)

- effacement of architecture by dilated sinuses

- capsular / pericapsular fibrosis and inflam is common

 

Lymph node: fibrotic capsule, massive dilatation of sinuses filled with characteristic histiocytosis with large nuclei and prominent nucleoli.

•Histiocytes: large with abundant pale cytoplasm showing emperipolesis.

•Positive: S100, histiocytic markers (CD68, CD163, CD4, CD11c, CD33, fascin), Cyclin D1 (often aberrantly expressed in the nuclei of clonal / neoplastic histiocytic proliferations), OCT2

•Negative: CD1a, CD207 (Langerin), BRAF V600E.

•Numerous plasma cells in the background (polytypic); helpful feature in extranodal sites.

•Frequently contain numerous IgG4 positive plasma cells; DDx IgG4-related disease.

__________________________________________

Genes: Negative for clonal IgH or TCR gene rearrangements.

•Polyclonal by HUMARA assay.

•Lack BRAF V600E mutations.

•Rare cases with NRAS/KRAS mutations recently reported.

__________________________________________

IHC: Oil red O shows lots of neutral lipid in the histiocytes, which are also strongly (+) for S-100 and CD68, PLAP+, but negative for CD1a and EBV

- OCT2 is a sensitive (+ in 97%) marker for abnormal histiocytes of Rosai-Dorfman disease

-- oct2 is + in 7% of LCH and 0% of ECD

__________________________________________

EM: histiocytes in the sinuses have extensive pseudopodia and lack Birbeck granules

__________________________________________

DDx:

- Reactive lymph node with sinus histiocytosis

- Hemophagocytosis

- Langerhans cell histiocytosis

__________________________________________

Tx: usually has fast and spontaneous relapse

- chemo may be helpful

__________________________________________

Px: Generally regarded as a non-neoplastic, reactive process with self-limited/indolent disease course, especially in classical (nodal) form.

•5-10% of pts may die of disease due to organ involvement or immunologic abnormalities.

 

 

 

Rosai-Dorfmann dz

* more prominent in extranodal sites

Touch prep from patient with Rosai Dorfman, histiocyte with abundant eosinophilic cytoplasm with ingested matieral. Cell was CD14+, CD68+, S100+, and CD1a- [6]

Rosai-Dorfman disease [6]. Looks vaguely whorled from low power

Rosai-Dorfman disease, S100 staining nucleus and cytoplasm, brings out emperipolesis [6]

 

Kimura disease

 

Endemic in Asia; presents as mass lesion in head / neck or major salivary glands usually in males

- has features that overlap c Angiolymphoid hyperplasia with eosinophilia (ALHE); except AHLE is mostly in the skin of white girls (no lymphadenopathy)

 

Micro: LNs have marked germinal center hyperplasia (some of which are progressively transformed)

- germinal centers have lots of BVs, interstitial fibrosis, and proteinaceous material, sometimes c eosinophilic abscesses

- see some paracortical sclerosis c hyalinized vessels

 

Kimura disease with polykaryotes

 

Castleman disease

 

aka giant LN hyperplasia

 

- similar labs as angioimmunoblastic lymphadenitis

May be solitary or multicentric

-- solitary MC presents in mediastinum and is asymptomatic (though can have sx if plasma cell type)

-- multicentric is nearly always plasma cell type and has generalized lymphadenopathy c spleen

- multiple germinal centers in 1 follicle (aka twinning or atretic GC)

- lollipop sign - radial penetrating arterioles

- onion skinning: concentric layers of mantle zone lympocytes

 

Nonlymphoid cells are involved in pathogenesis, such as follicular dendritic cells; and follicular dendritic cell tumors may develop

 

2 flavors: hyaline-vascular type or plasma cell type

 

1) Hyaline-vascular / solitary / unicentric type

Large follicles c lots of BVs and hyalinization or plasma cells  in paracortex in mass of lymph tissue that may look like a Hassal corpuscle

- has vesicular cells in hyalinized area that are follicular dendritic cells (+ CD21/23/35)

- surrounded by concentric layers of lymphs (like a mantle zone) which looks like onion skin

- sinuses are absent

- lymphoid sub-subtype has larger mantle zone and smaller germinal center

- no assoc c HHV-8

- tx is surgery

- Px good

 

2) Plasma cell / diffuse / Multicentric type

- aka Multicentric castleman dz

Lots of plasma cells in interfollicular tissue, possibly c Russell bodies

- has amorphous acidophilic material (probably fibrin) and no hyaline-vascular changes

- assoc c HHV8 (sometimes seen c Kaposi sarcoma) which causes inc serum IL-6 (HHV-8 encodes IL-6), POEMS syndrome, HIV, Wiscott-Aldrich syndrome, myasthenia gravis, pemphigus

- inc freq of plasmablastic lymphoma, Kaposi sarcoma, primary effusion lymphoma

Tx: chemotherapy

Px: Poor

 

Interfollicular plasmacytoid monocytes (+) CD123

 

 

Castleman dz, lollipop sign

Castleman dz, hyaline vascular variant with "twinning" with 2 or more atrophic GCs (white arrows)

HHV8+ multicentric Castleman disease. A. B-cell follicle with a regressed, partially hyalinized germinal center. B. Mantle zone has scattered plasmablasts. C. B-cell fiollicle with partial hyalinization of the germinal center with an attenuated mantle zone. D. Germinal center with numerous plasmablasts

Rheumatoid Arthritis-Related Lymphadenopathy

 

-

Sarcoid Lymphadenopathy

 

-

 

Dermatopathic Lymphadenitis (DL)

 

- aka lipomelanosis reticularis of Pautrier, or dermatopathic lymphadenopathy

 

Nodular paracortical hyperplasia secondary to generalized dermatitis c pruritis, usually c exfoliation (rarely occurs without assoc skin dz or rash)

 

Micro: paracortical aggregates of histiocytic / dendritic cells, including Langerhans cells and melanin-containing macrophages

- inc T cells in cortex / paracortex, Langerhans (LC) / interdigitating dendritic cells (IDC) c melanin-laden macrophages

- interdigitating dendritic cells c elongated, twisted nuclei c nuclear grooves, pale chromatin, and lots of eosinophilic cytoplasm

- post-capillary venules may be prominent

- has pale nodular paracortical areas

- see peripheral blood eosinophilia

 

IHC: (+) S100, Fascin (IDCs)

-  CD1a and Langerin highlights the Langerhans cells

- Fontana-Masson can highlight melanin pigment

 

 

DDx: Mycosis fungoides (T cell ag loss, TRB or TRG rearranged, and vascular prolif)

- Langerhans cell histiocytosis (LCH) when florid -- LCH involving lymph nodes shows intrasinusoidal (not solely paracortical) distribution with sinusoidal distention; to help differentiate, Cyclin D1 (and p-ERK) are expressed by neoplasatic cells of LCH, but not significantly by reactive Langerhans cell proliferations, and BRAF V600E is positive in ~50% of LCH

 

 

 

 

 

 

 

Hemophagocytic lymphohistiocytosis (HLH)

-aka macrophage activation syndrome or hemophagocytic syndrome [9]

 

Caused by systemic activation of macrophages and CD8 Tc cells, and assoc c T-cell lymphomas esp subcutaneous panniculitis like T-cell lymphoma

- macrophages eat up progenitor cells in BM and other stuff in peripheral tissues and release inflammatory mediators (TNFa, IL-6/12) that causes systemic inflammation leading to cytopenias and sx that look like shock

- may be genetic, in which case Tc and NK cells are not made properly and cytotoxic granules are released willy-nilly into circulation

- can also be caused by viruses, T cell lymphoma, x-linked syndrome

__________________________________________

Criteria (need 5 of 8):

Clinical: Fever, hepatosplenomegaly

 

Hematologic: Cytopenias (>=2 of 3), Hemophagocytosis

 

Serum values: Hypertriglyceridemia, Hypofibrinogenemia, Hyperferritinemia

 

Immunologic: Low or absent NK function, Elevated soluble CD25

 

Additional: Molecular demonstration of known gene mutation, Presence of a familial disease

__________________________________________

Severely ill patients, any age

- clinically there is a differential with an acute leukemia

- fever hepatosplenomegaly, LFT abnormalities, adenopathy, other constitutional sx

 

Disseminated macrophage proliferation and activation

- biologically it is an abnormal function of NK cells and T-cells

- macrophage proliferation and activation with exuberant cytokine release ("cytokine storm")

 

May be primary (inherited) or secondary

 

Familial Lymphohisitocytosis (primary lymphohistiocytosis)

- presents in infancy or early childhood

- mutations in several genes known (perforin, MUNC13-4, Syntaxin)

- similar syndromes occur in other immunodeficiencies (XLP, Chediak-Higashi, Griscelli syndrome)

 

Secondary - essentially all adult hemophagocytic syndromes are secondary

- infection associated - viral (EBV), bacterial fungal protozoal

- malignancy-associated (paraneoplastic from Hodgkin lymphomas)

= autoimmune-associated -- esp juvenile rheumatoid arthitis, "macrophage activation syndrome"

 

__________________________________________

Micro: bone marrow biopsies show histiocytic hyperplasia with marked hemophagocytosis

- findings are similar regardless of underlying cause

- look closely for underlying lymphoma in adults

__________________________________________

DDx: neoplastic hisitocytic disorders

- large cell lymphoma

- reactive increase in BM histiocytes / monocytes (increased cell turnover, MDS, MPN, granulomas, histiocytic hyperplasia associated with lymphoma, fat necrosis (post-chemotherapy), growth factor therapy)

__________________________________________

Px: Fulminant clinical course, poor without treatment

__________________________________________

Tx: immunosuppression and cytotoxic agents, sometimes may need bone marrow transplant

- without therapy, high mortality rate

 

 

Hemophagocytic lymphohistiocytosis (HLH)

Clinical and Laboratory criteria for the diagnosis of HLH [9]

Florid HLH [13]. Bone marrow aspirate with markedly increased histiocytes with prominent hemophagocytosis with ingestion of RBCs and neutrophils (usually it is not thils florid, will probably only see 1-2 histiocytes eating blood)

Lymphadenopathy Associated with Joint Protheses

 

-

Lipid-Associated Lymphadenopathy

 

-

Lymphadenopathy Secondary to Drug-Induced Hypersensitivity Syndrome

 

-

IgG4-Related Disease

 

-

Immunodeficiency-Associated Lymphoproliferations

Overview of Immunodeficiency-Associated Lymphoproliferative Disorders

 

-

ALPS

 

Autoimmune lymphoproliferative syndrome (ALPS)

 

Germline (sometimes somatic) mutations of FAS (TNFRSF6), FASL, or CASPASE gene that causes splenomegaly, hyperIgG, and autoimmune sx mostly in kiddos

- inc CD3+CD4-CD8- (double negative) alpha/beta T cells

 

Micro: paracortical expansion by smaller alpha-beta double negative T-cells c larger immunoblasts that can mimic lymphoma

- cells are CD45RO negative, which makes them cirgin T-cells

- florid follicular hyperplasia

- can have RDD-like changes

lymphoid hyperplasia in T-cell areas of spleen

 

 

ALPS IHC: paracortical T-cells are negative for CD45RO, CD4 and CD8, looks like some aberrent expression, but it is NOT! Be very careful of diagnosing PTCL in young patients!

 

ALPS - pt with marked splenomegaly, protuberant abdomen and marked cervical LAD , biopsy shows some reactive follicles with abundant paracortical expansion [4]

Immunomodulating Agent-Associated Lymphoproliferative Disorder

 

-

Posttransplant Lymphoproliferative Disorder, Early Lesions and Polymorphic

 

-

Posttransplant Lymphoproliferative Disorder, Monomorphic

 

-

Nonhematopoietic Proliferations in Lymph Node

Epithelial Inclusions in Lymph Node

Nevus Cell Inclusions in Lymph Node

Vascular Transformation of Lymph Node Sinuses

Angiomyamatous Hamartoma

Palisaded Myofibroblastoma

Metastatic Kaposi Sarcoma

Epithelial Inclusions in Lymph Node

 

-

Nevus Cell Inclusions in Lymph Node

 

-

Vascular Transformation of Lymph Node Sinuses

 

-

Angiomyamatous Hamartoma

 

-

Palisaded Myofibroblastoma

 

-

Metastatic Kaposi Sarcoma

-

Spleen

Note: Primary lymphoid organs = BM and thymus

- site of lymphocyte birth and maturation by a process that does not involve antigens; have no follicles and make mature naive lymphocytes

 

Secondary lymphoid organ (LNs, spleen, MALT) activate naive lymphocytes with antigen and have follicles

Embryology

 

Found @ ~5 WGA, red and white pulp distinguished at 9 mo GA

- functions as site of development of blood cells until ~6 mo GA (but hematopoiesis does not occur in spleen, just development)

- accessory spleens seen in ~ 1/4 of autopsies

- immotile cilia syndrome assoc c polyspenia

- lots of apoptosis in germinal centers of B-cell follicle, and is also T cell maturation

 

Anatomy / Physiology

 

Covered by a capsule and peritoneum, c dense irreg connective ittsue (has smooth muscle in some animals which can contract and give blood in emergencies)

- Splenic artery (from celiac artery) goes into hilum and gives rise to BVs from capsule (trabecular arteries and veins) supply blood to red pulp

- arteries leaving the capsule engulfed by periarteriolar lymphoid sheath (PALS), which goes into a white pulp nodule where it is then called the central artery (follicular arteriole)

- when central artery leaves the white pulp becomes the penicillar artery, which end as capillaries ensheathed by macrophages

 

 

- 90% of RBC removal occurs in the spleen. Cells removed include:

Senescent cells

Cells with decreased deformability

Opsonized cells

Cells with inclusions that cannot be removed by grooming

Cells with  intracellular parasites (malaria, babesia, etc.)

Cells with crystals (e.g. Hb C) or increased viscosity (sickled cells)

Severely damaged or misshapen RBCs are removed by the liver

 

The function of littoral cells is to maintain a healthy erythron.

They do this in three ways: grooming, pitting, and culling.

Grooming is the removal from the cell’s surface of excess:

 lipids ; cholesterol ; and proteins

Grooming prevents the formation of target cells, stomatocytes, acanthocytes

 

Pitting is removal of intracellular particles from RBC while leaving the cell intact.

Inclusions removed include:

 Howell-Jolly bodies ;  Heinz bodies ; Pappenheimer bodies ;  intracellular parasites

“Bite cells” may be the result of pitting

 

Culling is removal of damaged or senescent RBCs, known as erythrophagocytosis

- Aging RBCs undergo morphologic changes that signal senescence.

- Protein Band 3 clusters in cell membrane, appears to be “non-self”

- RBCs are opsonized

Littoral cells phagocytize the opsonized cells.

 

There are two major factors responsible for age related changes in RBCs that will initiate phagocytosis in the spleen:

 

Decrease in enzyme activity

 

ATP becomes less available as EM pathway shuts down

Na + /K + pump less efficient --> More internal Na+; Less internal K +

Greater Internal viscosity

- Phosphogluconate pathway shuts down --> Less G6PD activity causing more reactive O2 species, more unstable hemoglobin

- Luebering-Rapaport Pathway shuts down --> Less 2, 3 DPG made, Oxygen affinity increases

 

Repeated passes through the spleen

 

reduces membrane phospholipids - Cholesterol content reduced ; Membrane becomes rigid

- Parts of the cell membrane are removed: MCHC increases ; MCV decreases (younger cells are larger) ; Cells become more spheroidal

- Decreased sialic acid --> Cells become more agglutinable

 

Spleen also serves as a reservoir for platelets

- 30% of circulating platelets are sequestered in the spleen

-- allows immediate release to the circulation if needed

Splenomegaly (increase in the size of the spleen) can cause increased sequestration of platelets

Causes of splenomegaly: Cirrhosis of the liver; Leukemia or lymphoma

 

Splenectomy

can occur two ways: Surgery ; Auto-splenectomy

Patients with no spleen have an increased risk of infections, particularly from encapsulated bacteria.

 - Peripheral blood findings in splenectomized patients:

Codocytes (Target Cells) ; Howell-Jolly bodies ; Acanthocytes ; Stomatocytes ; Spherocytes

 

Indications for Splenectomy

•Trauma/Incidental

•Myeloproliferative Neoplasms

•Lymphoproliferative Disorders

•Staging Laparotomy

•Hereditary Spherocytosis

•Splenic Lipidoses

•Autoimmune Disorders

•Diagnosis of Splenic Mass (CT, MRI)

•“Hypersplenism”

 

 

Histology

 

Lacks cortex and medulla

The white pulp is involved with immune surveillance.

It is composed of  nodules called  Malpighian corpuscles

These corpuscles are composed of "lymphoid nodules" (or "follicles") which are rich in B-lymphocytes, and periarteriolar lymphoid sheaths (PALS) which are rich in T lymphocytes

- irrigated by central artery (surrounded by PALS) which gives off radial arterioles, that end in marginal sinus (goes around the white pulp)

- marginal sinus and central artery blood go into penicillar arteries ending in capillaries surrounded by macrophages (macrophage-sheathed capillaries), which can drain into splenic sinusoids (closed circulation) or red pulp stroma (open circulation)

 

The red pulp is where the red blood cells are filtered.

It  consists of long, tortuous sinuses which the red blood cells must filter through

Red pulp = penicillar arterioles, macrophage-sheathed capillaries, (splenic) cords of Billroth [reticular cells forming stroma], and splenic (venous) sinusoids, and all types of blood cells stored here

- cords of Billroth lined by macrophages, plasma cells and RBCs(?), separates sinusoids

- sinusoids surrounded by macrophages that filter old RBCs and circulating bugs from the blood (similar to Kupffer cells in liver)

-- sinusoids surrounded by ringed-network of reticular fibers and basal lamina

 

Post-splenectomy, may see Howell-Jolly bodies (nuclear remnants), target cells, and thrombocytosis

 

***T cells found in structures that begin with "P" = PALS in spleen and Paracortex of LNs; B cells found in follicles - follicles of cortex in LNs and follicles of white pulp in spleen***

 

Gross

Weigh / measure, assess hilar vasculature, LNs

- photograph capsular abnormalities

- section at 1 cm, photograph abnormalities

- sample splenic parenchyma (1-2 sections if normal, more if abnormal)

- submit hilar LNs

- Sample gross lesions (lacerations, cyst wall, mass lesions)

- if lymphoma suspected, do touch prep and flow cytometry / cytogenetics

Splenic circulation

Normal spleen. Slice showing intact capsule, no thrombi in vessels, red pulp with small nodules of white pulp

Splenogonadal fusion typically occurs with the left testis

Spleen capsule [5] - is the only thing that stands between the entire blood volume or your spleen and the abdominal cavity

 

Diffuse Splenic Lesions

White Pulp - Miliary Pattern

•Reactive lymphoid hyperplasia.

•Granulomas.

•Small B-cell lymphomas (e.g. MZL, CLL, FL).

 

Diffuse WP miliary pattern

•Splenic marginal zone lymphoma.

•Micronudular variant of T-cell histiocyte-rich large B-cell lymphoma.

 

Diffuse RP pattern

•Hairy cell leukemia.

•Splenic diffuse red pulp small B-cell lymphoma.

•Hairy cell leukemia variant.

•Hepatosplenic T-cell lymphoma.

 

 

Red Pulp - Diffuse "beefy red"

•Storage disorders.

•Extramedullary hematopoiesis.

•Myeloid and lymphoid leukemias (e.g. AML, MPN, hairy cell leukemia).

•Histiocytic proliferations

 

Focal/multifocal Splenic Lesions

Large cell lymphoma

Hodgkin lymphoma

Pseudotumoral lesions (IPT, hamartoma, SANT)

Vascular lesions/tumors

Metastatic tumors (carcinoma, sarcoma)

Reactive (cysts, peliosis, infarcts)

 

Extramedullary hematopoiesis

When the bone marrow is compromised or overwhelmed and cannot produce enough red blood cells to support the erythron, the spleen will take over erythropoiesis.

Causes: bone marrow infiltration from myelofibrosis or leukemia

- Clinical signs of a compromised bone marrow: Nucleated RBCs ; Teardrop cells

 

Splenic Injuries

Mechanical

Trauma - laceration, hemorrhage, "fractured spleen"

- implants can grow into splenic tissue ("splenosis")

 

Infarction - embolic, sickle cell disease, torsion

 

Congestion - Acute, chronic (with fibrosis -- cirrhosis, portal HTN)

 

Atraumatic splenic rupture

- Neoplastic - 30% -- homorrhagic / vsscular

- Infectious 27% -- EBV, malaria

- inflammatory 20% -- pancreatitis, vasculitis

- drug - tx 9% -- GCSF included

- Mechanical 7% -- pregnancy, cirrhosis

- Normal spleen 6%

Splenic infarct with necrosis with surrounding organization

Splenosis - small splenules with a capsule with prominent EMH

Splenic fracture from MVA

Autoimmune Splenitis

 

Splenic capsule is thick, known as hyaline perisplenitis (or sugar-icing)

- mainly a white pulp problem, centered around blood vessels, with white pulp hyperplasia and eventually scarred blood vessels

- the red pulp is fairly normal in autoimmune disorders involving the spleen

 

DDx: may have some cellular breakdown that looks a little like Kikuchi-Fujimoto dz

Autoimmune splenitis - forms nodule around vessel that replaces the white pulp. First shows onion-skinning, then these scar-like vessels

Splenic Cysts

 

Secondary Cysts (eg post-trauma

- lack lining, thin-walled, don't recur

 

Primary cysts

- thick fibrous wall

- squamous, mesothelial, or rarely transitional epithelium (may be denuded)

- recurrence risk if incompletely removed

- can cause elevation in CA19-9, CEA

 

Parasitic cysts (echinococcal) - contain scolices

Primary splenic cyst

Reactive abnormalities of the red and white pulp: consumption [5]

 

Autoimmune hemolytic anemia

 

Immune thrombocytopenic purpura

- splenectomy usually follows exhaustion of pharmacologic options

 

Hemophagocytic lymphohistiocytosis (HLH)

- with or without malignancy (often lymphoma)

- splenectomy often in search of lymphoma dx

Splenic Vascular Proliferations

Non-hematolymphoid/pseudotumoral lesions presenting as splenic mass:

Splenic cysts

Peliosis

Inflammatory pseudotumor

Splenic hamartoma

Vascular tumors (cord capillary hemangioma, littoral cell angioma)

Sclerosing angiomatoid nodular transformation

Metastatic tumors

Storage disorders

 

Splenic Hamartoma

 

•Tumor-like proliferation composed of structurally disorganized mature red pulp elements (cordal histiocytes, vasculature, myoid cells).

•Uncertain etiology.

•Rare (0.2%); usually incidental finding.

•M=F; diagnosed at all ages (11 mo to 86 yr).

•Majority pts asymptomatic.

•Splenectomy curative.

- IHC: CD31+, CD68+, CD8+


Cord Capillary Hemangioma

 

•Rare tumor with clinical and morphologic overlap with hamartoma.

•Initially considered a morphologic variant of hamartoma (“capillary-rich” variant).

•Different vascular composition from hamartoma (CD8-/CD34+).

•Demonstrated to be clonal and different from hamartoma.

Splenic Hamartoma

 

- has same IHC pattern as normal sinuses

Sclerosing Angiomatoid

Nodular Transformation (SANT)

 

•Non-neoplastic vascular lesion with angiomatoid nodules associated with fibrosis

•May represent reaction to inflammation, tumor, and hemorrhage

•Solitary well-demarcated mass with central scar

•Small vessels with variable phenotype: sinusoidal (CD8+/CD31+/CD34-); capillary-like (CD8-/CD31+/CD34+); venous (CD8-/CD31+/CD34-).

•Some cases show increased IgG4 plasma cells (not considered part of spectrum of IgG4-related diseases)

SANT

SANT [5]. Grossly it can look pretty scary.

Littoral Cell Angioma

 

•Benign vascular neoplasm of red pulp sinus-lining cells with histiocytic and endothelial cell differentiation.

•Rare; usually incidental.

•Multiple spongy lesions throughout the spleen.

•M=F; all age groups.

•Splenectomy curative.

•Frequent association with visceral malignancies. – Peckova K et al. Histopathology 2016;762-774.

 

IHC: CD31+/CD68+, unlike normal sinuses, are CD8-, CD21+/-, CD34-

Splenic lymphangioma

 

Should stain with normal lymph vessel markers (CD31+, D2-40+)

Splenic lymphangioma [5]

Splenic inflammatory pseudotumor-like FDC tumor

 

Its name is inversely proportional to its incidence

- May need multiple FDC marker panel,

- generally EBV+,

= negative for SMA and CD68. Female predominance, systemic symptoms, can recur

 

EBV positivity seen in the stromal cells

Splenic inflammatory pseudotumor-like FDC tumor. May need multiple FDC marker panel, generall EBV+, should be negative for SMA and CD68. Female predominance, systemic symptoms, can recur

General rule: lymphomas that involve the LNs usually involve the white pulp of spleen, and those that involve the blood and BM involve the red pulp [5]

Splenic Marginal Zone Lymphoma (SMZL)

 

•First described by Schmid et al in 1992

(Am J Surg Pathol 1992;16:455-466).

•<2% of lymphoid malignancies.

•Middle aged to elderly pts without gender predominance.

•Associated with HCV (S. Europe), cryoglobulinemia type II, autoimmune disorders.

 

Splenomegaly without lymphoadenopathy (although sometimes the spleen can be of normal size!!), lymphocytosis (+/- villous lymphocytes), cytopenias

•BM with intrasinus involvement

- blood commonly involved, see villous lymphocytes

•Peripheral LAD uncommon

•Autoimmune phenomena (20%)

•Monoclonal paraprotein, <20g (33%)

•Median survival 10 years

•May transform to LBCL

 

Micro: biphasic pattern with prominent marginal zone in spleen (mimics the splenic white pulp)

- medium-sized cells with pale cytoplasm

 

By definition, the lymph nodes (LNs) involved by SMZL do not show the prominent zonation that is seen in the spleen

 

IHC:

Positive:

•Pan-B-cell antigens (CD19, CD20, CD22, BSAP/PAX-5), BCL-2, CD24, CD27, IgM, IgD

Variable:

•CD5 (20%), CD23 (30%); CD5/23 co-expression rare

CD5 expressed in up to 20%

- cases of SMZL that are CD5+ are similar to the classic CD5- variant except tend to have higher lymphocyte cound at dx and more diffuse BM infiltration

•DBA.44 (75%), CD11c (50%), CD25 (25%)

•CD138, kappa/lambda (PC differentiation)

•IRTA1 (25-50%), MNDA (70%)

Negative

•CD10, BCL-6, CD43 (important negative finding), cyclin D1, SOX11, LEF1, CD103, annexin A1

 

Genes: cytogenetic / genotype studies are not usually necessary for the diagnosis, though should have clonal Ig gene rearrangement

 Allelic loss of 7q31-32 (30%).

- clonal IgH R, IgH mutations

•Small number of cases show t(2;7)(p12;q21) CDK6-IgK; dysregulation of CDK6 gene at 7q21.

•Trisomy 3q (10-20%).

•17p deletion; p53 allelic loss.

•NO evidence of MALT lymphoma-associated translocations t(11;18)(q21;q21), t(14;18)(q32;q21), or t(3;14)(p13;q32).

 

A subset may have MYD88 mutations, so cannot use this to differentiate from LPL

 

Molecular Genetics

•NOTCH2 mutations (10-25%); may also be seen in small number of cases of MALT lymphoma and DLBCL.

•KLF2 mutations (10-40%); also found in other small B-cell lymphomas. (people aren't looking for this now)

•MYD88 mutations rare in SMZL; helpful to distinguish from LPL in cases with plasmacytic differentiation.

•NOTCH2, KLF2, and TP53 mutations reported to be adverse prognostic indicators based on limited data.

 

DDx:

Major diagnostic pitfalls and how to deal with them

- Hyperplastic splenic marginal zones -- nonclonal , here, genetic studies are critical!!! (FCIPS/genotypic studies), splenic marginal zones can be very prominent in many types of benign spleens

- Pale appearing marginal zone involvement by other types of NHL -- FL, MCL, other MZL

--- morphology: homogeneous centrocytes in FL

- Phenotype: SMZL typically are CD5-, CD10-, CD23-, CD43-, CyclinD1-, although cases studies by FCIPS are more often reported to be CD5 or CD10+

---- IgD positivity is typical but not a specific finding and not always found

 

Tx: splenectomy may be the treatment of choice even if stage IV

- regression of splenic lymphoma with villous lymphocytes after treatment of hepatitis C virus infection with interfreon (alone or in combination with ribavirin)

-- Dx not based on splenectomt

- Similar treatment failed in 6 patients with non-HCV associated SLVL

 

A recent study [Blood. 2016;128(21):2527-2532] has shown that direct-acting antiviral agents are able to induce lymphoma response in patients with HCV-associated indolent non-Hodgkin lymphoma

- the highest rate of lymphoma response (73%) was seen in pts with marginal zone lymphoma

 

SMZL

Histologically, SMZL mimics the white pulp

SMZL villous lymphocyte

SMZL involving a LN, showing cells with pale cytoplasm, zonation with not be present in the LN as it is in the spleen

A classic case of SMZL, with increased and enlarged white pulp nodules, with dark central cores and paler peripheral marginal zones, also infiltration of the red pulp with little nodules and cells in the cores.

A classic case of SMZL, at higher mag, see the darker central core with lighter marginal zone, with a larger number of smaller lymphs with less cytoplasm in the central cords, here there are too many lymphocytes in the red pulp to be considered normal

Classic SMZL, high mag showing the small lymphocytes of the central core in the white pulp nodule, and the cells in the marginal zone with more abundant pale cytoplasm that looks like normal splenic marginal zone cells and smaller lymphocytes in the red pulp

Some cases of SMZL have mostly or exclusively monophasic WP nodules, instead of biphasic WP nodules

Splenic marginal zone lymphoma,  involves the periphery of the white pulp nodules. paler region where cells are larger, have more cytoplasm and  more dispersed chromatin

Marginal zone lymphoma in a mesenteric lymph node Left - follicles iwth GC, smaller mantle zone and paler peripheral zone, high mag (right) shows difficult to tell where mantle zone ends and marginal zone begins, bottom shows cells with pale cytoplasm and dispersed chromatin

Splenic Diffuse Red Pulp Small B-cell Lymphoma

 

- the name kinda says it all

- a member of the splenic B-cell lymphoma/leukemia unclassifiable category (a provisional entity along with Hairy cell leukemia variant)

- involves the BM sinusoids (+/- interstitial and nodular) and PB, often with villous cytology (low level lymphocytosis, not marked like hairy-cell leuekmia variant)

- another indolent but incurable ML with responses following splenectomy

 

Dx'd in up to 10% of B-cell lymphomas in splenectomy specimens (spleen is usually huge)

- can see villous lymphs (like those in SMZL) in PB

- must see intrasinusoidal infiltration on BM

- spleen diffusely involved, but no follicular replacement, biphasic cytology or marginal zone infiltration

- lymphocytosis present but generally low, splenomegaly is fequent and may be massive

 

(+) CD20, DBA.44 IgG

(-) IgD, ANXA1, CD5/10/11c/23/25/103/123

 

Have low amt of IGHV gene somatic hypermutation

- lack del 7q and t(11:14), but TP53 frequently mutated

 

- indolent but incurable dz, splenectomy usually helps

Splenic diffuse red pulp small B-cell lymphoma

Splenic diffuse red pulp lymphoma [5] - high power shows angulated cells

Diffuse Large B-cell Lymphoma (DLBCL) Arising in the Spleen

 

•Variable incidence (11-34% of spleen lymphomas).

•Most cases represent secondary dissemination by systemic DLBCL.

•Primary lymphoma uncommon.

•Pts frequently present with acute fever, abdominal pain, B symptoms.

Patterns

Pattern A – Macronodular

•20/33 (61%) cases

•BCL6 positive

•Favorable outcome

 

Pattern B – Micronodular

•9/33 (27%) cases

•Resemble micronodular variant of T-cell histiocyte-rich large B-cell lymphoma

 

Pattern C – Diffuse

•4/33 (12%) cases

•Poor outcome

Splenic LBCL - Macronodular pattern

Myeloid Neoplasms

 

Ph* negative myeloproliferative neoplasms

•Polycythemia vera (PV)

•Essential thrombocythemia (ET)

•Primary myelofibrosis (PMF)

 

Chronic myeloid  leukemia, BCR-ABL1 positive

 

Acute Myeloid Leukemia

 

Systemic Mastocytosis

 

Ph(-) Myeloproliferative Neoplasm

Prefibrotic phase

•Mild to moderate splenomegaly

•Congestion of cords and sinuses

•Platelets sequestered in spleen -> splenectomy usually contraindicated (protective effect towards thrombocytosis).

 

 

Ph(-) Myeloproliferative Neoplasm Fibrotic Phase

•Marked splenomegaly.

•Myelofibrosis; leukoerythroblastosis.

•Extramedullary hematopoiesis (EMH): expansion of RP by erythroid, granulocytic, and megakaryocytic elements.

•Splenectomy performed for cytopenias.

•Post- PV MF, post-ET MF, PMF morphologically indistinguishable

 

PMF – diffuse red pulp involvement

PMF

References

 

1. Lecture from LASOP, Jan 18, 2020.

 

2. Medeiros. Lymph Nodes and Extranodal Lymphomas. 2018.

 

3. Sohani, Aliya. Reactive Lymphoid Hyperplasia: Diagnostic Pitfalls and how to avoid them.  Society for hematopathology. https://www.society-for-hematopathology.org/web/education-virtual-curriculum-view.php?video_id=421986562

 

4. Elaine Jaffe. Immunohistochemical Aids for the Diagnosis and Classification of Lymphoproliferative Disorders. https://www.society-for-hematopathology.org/web/education-virtual-curriculum-view.php?video_id=420007711

 

5. Gratzinger D. Spleen: Red, White, and Hungry for Blood. https://www.society-for-hematopathology.org/web/education-virtual-curriculum-view.php?video_id=422673258

 

6. Cook J. Introduction to Histiocytic Disorders. https://www.society-for-hematopathology.org/web/education-virtual-curriculum-view.php?video_id=414271529

 

7. YouTube video. Approach to the lymph node - Dr. Crane. https://www.youtube.com/watch?v=EbZGWXY3m-s

 

8. Natkunam Y. Immunodeficiency Associated Lymphoproliferative Disorders: Time for Reappraisal? Soc for Hemepath. https://www.society-for-hematopathology.org/web/education-virtual-curriculum-view.php?video_id=412839740

 

9. Ponnatt T et al. Hemophagocytic Lymphohistiocytosis. Arch Pathol Lab Med. Vol 146, 4/2022.

 

10.