Lymph node pathology

This article deals with non-haematologic malignant, i.e. metastases, and non-malignant lymph node pathology. An introduction to the lymph node is in the lymph nodes article.

Haematologic malignancies (in lymph nodes) are dealt with in other articles - see haematopathology and lymphoma.

Overview

Clinical:

• Lymphadenopathy.

Differential diagnosis:

• Infectious - fungal, mycobacterial, viral, protozoal (Toxoplasma), bacterial (Chlamydia, Rickettsia, Bartonella)).
• Neoplastic - lymphoma, carcinoma.
• Endocrine - hyperthyroidism.
• Trauma.
• Autoimmune - SLE, RA, dermatomyositis.
• Inflammatory - drugs (phenytoin).
• Idiopathic - sarcoidosis.

Overview in a table

Entity	Key feature	Other findings	IHC	DDx	Image
Non-specific reactive follicular hyperplasia (NSRFH)	large spaced cortical follicles	tingible body macrophages, normal dark/light GC pattern	BCL2 -ve	infection (Toxoplasmosis, HIV/AIDS), Hodgkin's lymphoma	image ?
Lymph node metastasis	foreign cell population, usu. in subcapsular sinuses	+/-nuclear atypia, +/-malignant architecture	dependent on tumour type (see IHC)	dependent on morphology, endometriosis (mimics adenocarcinoma), ectopic decidua (mimics SCC)	CRC metastasis Breast metastasis
Progressive transformation of germinal centers	large (atypical) germinal centers	poorly demarcated germinal center (GC)/mantle zone interfaces, expanded mantle zone	IHC to r/o nodular lymphocyte predominant Hodgkin lymphoma (NLPHL)	NLPHL, follicular hyperplasia	PTGC - very low mag.
Toxoplasmosis	large follicles; epithelioid cells perifollicular & intrafollicular	reactive GCs, monocytoid cell clusters, epithelioid cells	IHC for toxoplasma	NSRFH, HIV/AIDS, Hodgkin's lymphoma	TL - low mag.
Kikuchi disease (histiocystic necrotizing lymphadenitis)	No PMNs	histiocytes, necrosis	IHC for large cell lymphoma (CD30 + others)	SLE (has (blue) hematoxylin bodies in necrotic areas), large cell lymphomas	HNL - very high mag.
Cat-scratch disease	PMNs in necrotic area	"stellate" (or serpentine) shaped microabscesses, granulomas	B. henselae, Dieterle stain	HIV/AIDS, NSRFH	Cat scratch - very low mag.
Dermatopathic lymphadenopathy	melanin-laden histiocytes	histiocytosis	S100+ve (interdigitating dendritic cells), CD1a+ve (Langerhans cells)	cutaneous T-cell lymphoma	DL - intermed. mag.
Kimura disease	eosinophils	angiolymphoid proliferation (thick-walled blood vessels with hobnail endothelial cells)	IHC ?	Langerhans cell histiocytosis, drug reaction, angiolymphoid hyperplasia with eosinophilia	Kimura disease - very high mag.
Langerhans cell histiocytosis	abundant histiocytes with reniform nuclei	often prominent eosinophilia	S100+, CD1a+	Kimura disease (eosinophilia), Rosai-Dorfman disease	LCH - very high mag.
Rosai-Dorfman disease	sinus histiocytosis	emperipolesis (intact cell within a macrophage)	S100+, CD1a-	Langerhans cell histiocytosis	RDD - very high mag.
Systemic lupus erythematosus lymphadenopathy	(blue) hematoxylin bodies	necrosis, no PMNs	IHC for large cell lymphoma (CD30 + others)	Kikuchi disease, large cell lymphomas	SLEL - high mag.
Castleman disease, hyaline vascular variant	thick mantle cell layer with laminar appearance ("onion skin" layering)	hyaline (pink crap), lollipops (large vessels into GC), no mitoses in GC	IHC - to r/o mantle cell lymphoma	mantle cell lymphoma, HIV/AIDS	CD - intermed. mag.
Castleman disease, plasma cell variant	thick mantle cell layer	sinus perserved, interfollicular plasma cells, mitoses in GC	HHV-8	HIV/AIDS	image ?
Intranodal palisaded myofibroblastoma	spindle cells with nuclear palisading	RBC extravasation, fibrillary bodies with a central vessel "amianthoid fibers"	SMA+, cyclin D1+	schwannoma	IPM - very high mag.

Follicular lymphoma vs. reactive follicular hyperplasia

Factors to consider:

	Reactive follicular hyperplasia	Follicular lymphoma
Follicle location	cortex	cortex and medulla
Germinal center edge	sharp/well-demarcated	poorly demarcated
Germinal center density	well spaced, sinuses open	crowded, sinuses effaced/ compressed to nothingness
Tingible body macrophages	common	uncommon
Germinal center light/dark pattern	normal	abnormal

Lymph node metastasis

General

• Determination of lymph node status is one of the most common indications for the examination of lymph nodes.
• It is a good idea to look at the tumour (if available) ...before looking at the LNs for mets.
• Lymph node metastasis, in the absence of other metastases, often up-stage a cancer from stage II to stage III.

Gross

• Outside:
  • "Large" - size varies by site.
    • Neck >10 mm.
  • Shape - round more suspicious than oval.
• Sectioned:
  • White firm lesion with irregular border - classic appearance.
  • Non-fatty hilum.

Microscopic

Features:

• Foreign cell population - key feature.
  • Classic location: subcapsular sinuses.
• +/-Cells with cytologic features of malignancy.
  • Nuclear pleomorphism (variation in size, shape and staining).
  • Nuclear atypia:
    • Nuclear enlargement.
    • Irregular nuclear membrane.
    • Irregular chromatin pattern, esp. asymmetry.
    • Large or irregular nucleolus.
  • Abundant mitotic figures.
• +/-Cells in architectural arrangements seen in malignancy; highly variable - dependent on tumour type and differentiation.
  • +/-Gland formation.
  • +/-Single cells.
  • +/-Small clusters of cells.

Notes:

1. Cytologic features of malignancy may not be present; some tumours, e.g. gallbladder carcinoma, do not always have overt cytologic features of malignancy.
   • The diagnosis is based on the fact that they are foreign to the lymph node and architecturally consistent with a well-differentiated malignancy.
2. Lymph node metastases in sarcomas are uncommon; they are seen in <3% of cases.
3. Fatty lymph nodes (esp. fatty hilus) are less likely to harbor metastases.

DDx - mimics of metastatic disease:

• Endometriosis.
• Ectopic decidua.
• Endosalpingiosis.
• Melanocytic nevus - intracapsular or within the trabeculae.
• Dermatopathic lymphadenopathy.^{[citation needed]}

Images

• 

  Breast carcinoma LN metastasis (WC)

• 

  Thyroid carcinoma LN metastasis (WC)

• 

  Colorectal carcinoma LN metastasis (WC)

• 

  Melanoma in a lymph node. (WC)

Mimics

• 

  Decidua in a LN - low mag. (WC)

• 

  Decidua in a LN - high mag. (WC)

• 

  Endometriosis in a LN - intermed. mag. (WC)

• 

  Endosalpingiosis in a LN - intermed. mag. (WC)

• 

  Endosalpingiosis in a LN - very high mag. (WC)

Kaposi sarcoma

Main article: Kaposi sarcoma

• One of the few non-lymphoid primary lymph node tumours.

Melanocytic nevi

Main article: Melanocytic lesions

See: Dermatopathic lymphadenopathy.

• Benign melanocytic nevi can be found in lymph nodes.

Progressive transformation of germinal centers

Main article: Progressive transformation of germinal centers

• Abbreviated as PTGC.

Reactive follicular hyperplasia

General

• Many causes - including: bacteria, viruses, chemicals, drugs, allergens.
  • In only approximately 10% can definitive cause be identified.

Microscopic

Features:

• Enlarged follicles, follicle size variation - key feature with:
  • Large germinal centers (pale on H&E).
    • Mitoses common.
    • Variable lymphocyte morphology.
    • Tingible-body macrophage (large, pale cells with junk in the cytoplasm).
    • Germinal centers (GCs) have a crisp/sharp edge.
    • Normal dark/light variation of GCs; superficial aspect light, deeper aspect darker.
  • Rim of small (inactive) lymphocytes.

IHC:

• BCL2 -ve.

Image: Normal lymph node (umdnj.edu).

Diffuse paracortical hyperplasia

General

• Benign.

Microscopic

Features:

• Interfollicular areas enlarged - key feature.
  • T cell population increased.
  • Plasma cells.
  • Macrophages.
  • Large Reed-Sternberg-like cells.

Sinus histiocytosis

General

• Benign.
• Non-specific finding.

Microscopic

Features:

• Sinuses distended with histiocytes - key feature.
• Plasma cells increased.

DDx:

• Rosai-Dorfman disease - histiocyte nuclei large (~2-3x lymphocyte) and round with a prominent nucleoli.
• Dermatopathic lymphadenopathy - histiocytes have (melanin) pigment.

Sign out

• The finding is often ignored; may be signed out as morphologically benign lymph nodes.

Kikuchi disease

• AKA histiocytic necrotising lymphadenitis (HNL).
• AKA Kikuchi-Fujimoto disease.

General

• Rare disease that may mimic cancer, esp. lymphoma.
  • May cause fever & systemic symptoms.

Epidemiology:

• Usually <40 years old.
• Asian.
• Female:Male = 3:1.

Treatment:

• Usually self-limited.
• Oral corticosteroids.

DDx:

• Non-Hodgkin lymphoma.
• Systemic lupus erythematosus.
  • Have hematoxyphil bodies in necrotic foci.
    • Dark blue irregular bodies on H&E.

Micrograph

Features (the three main features - just as the name suggests):

• Histiocytes.
  • May be crescentic.
• Necrosis (due to apoptosis) - paracortical areas.
  • Necrosis without neutrophils - key feature.
• Lymphocytes (CD8 +ve).
• Plasmacytoid dendritic cells.

Notes:

• Dendritic cell - vaguely resembles a macrophage:
  • Long membrane projections - key feature.
  • Abundant blue-grey cytoplasm, +/- ground-glass appearance.
  • Nucleus: small, ovoid, usu. single nucleolus.

Images

• 

  Kikuchi disease - intermed. mag. (WC)

• 

  Kikuchi disease - high mag. (WC)

• 

  Kikuchi disease - very high mag. (WC)

www:

• Kikuchi disease - several crappy images (upmc.edu).

IHC

• CD68 +ve.
• CD8 +ve - usu. predominant.
• CD4, CD20, CD3, and CD30 - mixed.
  • Done to excluded lymphoma; esp. large cell lymphomas; should show a mixed population of lymphocytes.
• Others:
  • CD56 -ve.

Systemic lupus erythematosus lymphadenopathy

General

• Lymphadenopathy associated with systemic lupus erythematosus (SLE).

Microscopic

Features:

• Necrosis.
• Hematoxylin bodies (in necrotic foci).
  • Dark blue irregular bodies on H&E.

DDx:

• Kikuchi disease.

Images

• 

  SLE lymphadenopathy - high mag. (WC)

• 

  SLE lymphadenopathy - very high mag. (WC)

Castleman disease

• AKA angiofollicular lymph node hyperplasia, giant lymph node hyperplasia.
• Abbreviated CD.

General

• Benign.
• Hyaline vascular variant - a pathology of the follicular dendritic cells.

Classification

CD is grouped by histologic appearance:

1. Hyaline vascular (HV) variant (described by Castleman).
   • Usually unicentric.
   • Typically mediastinal or axial.
   • More common than plasma cell variant; represents 80-90% of CD cases.
   • May be associated with follicular dendritic cell neoplasia.
2. Plasma cell (PC) variant.
   • Usually multicentric, may be unicentric.
   • Abundant plasma cells.
   • Associated with HHV-8 infection (the same virus implicated in Kaposi's sarcoma).

Notes:

• The subclassification of CD is in some flux. Some authors advocate splitting-out HHV-8 and multicentric as separate subtypes.

Microscopic

Hyaline-vascular variant

Features:

• Pale concentric (expanded) mantle zone lymphocytes - key feature.
  • "Regressed follicles" - germinal center (pale area) is small.
• "Lollipops":
  • Germinal centers fed by prominent (radially penetrating sclerotic) vessels; lollipop-like appearance.
• Two germinal centers in one follicle.
• Hyaline material (pink acellular stuff on H&E) in germinal center.
• Sinuses effaced (lost).
• Mitoses absent.

Images

• 

  CD HVV - "lollipop" sign - high mag. (WC)

• 

  CD HVV - showing expanded mantle zone - intermed. mag. (WC)

www:

• CD HVV - case 1 - several images (upmc.edu).
• CD HVV - case 2 - several images (upmc.edu).

Plasma cell variant

Features:

• Interfollicular sheets of plasma cells - key feature.
• Active germinal centers - mitoses present.
• Sinus perserved.

IHC

Hyaline-vascular variant:

• Stains to exclude mantle cell lymphoma:
  • Cyclin D1.

Plasma cell variant:

• HHV-8 +ve.

Cat-scratch disease

• AKA Cat-scratch fever.

General

• Infection caused Bartonella henselae, a gram-negative bacilla (0.3-1.0 x 0.6-3.0 micrometers) in chains, clumps, or singular.
• Treatment: antibiotics.

Clinical

Features:

• Usually unilateral.
  • May be disseminated in individuals with immune dysfunction.
• Contact with cats.

Micrograph

Features:

• Necrotizing granulomas with:
  • Neutrophils present in microabscess (necrotic debris) - key feature.
    • Microabscesses often described as "stellate" (star-shaped).
• +/-Multinucleated giant cells.

Notes:

• May involve capsule or perinodal tissue.

DDx of stellate abscess in lymph nodes - cat split:

• Cat-scratch disease.
• Sporotrichosis.
• Lymphogranuloma venereum.
• Tularemia.

Images:

• Cat-scratch disease (webpathology.com).
• Cat-scratch disease - high mag. (webpathology.com)
• CSD - very low mag. - showing serpentine shaped microabscesses (WC).
• CSD - high mag. - showing neutrophilic abscesses (WC).

Stains

• Warthin-Starry stain +ve.

IHC

• B. henselae IHC stain +ve - diagnostic.

Toxoplasma lymphadenitis

Main article: Toxoplasma

General

• Caused by protozoan Toxoplasma gondii.

Microscopic

Features:

• Reactive germinal centers (pale areas - larger than usual).
  • Often poorly demarcated - due to loose epithelioid cell clusters at germinal center edge - key feature.
• Epithelioid cells - perifollicular & intrafollicular.
  • Loose aggregates of histiocytes (do not form round granulomas):
    • Abundant pale cytoplasm.
    • Nucleoli.
• Monocytoid cells (monocyte-like cells) - in cortex & paracortex.
  • Large cells in islands/sheets key feature with:
    • Abundant pale cytoplasm - important.
    • Well-defined cell border - important.
    • Singular nucleus.
  • Cell clusters usually have interspersed neutrophils.

Images:

• Toxoplasmosis - low mag. (WC).
• Toxoplasmosis - high mag. (WC).

Notes:

• Monocytoid cells CD68 -ve.

IHC

• IHC for toxoplasmosis.

Dermatopathic lymphadenopathy

General

• Lymphadenopathy associated with a skin lesion - key feature.
• May be benign or malignant (e.g. T-cell lymphoma).

Microscopic

Features:

• Abundant histiocytes & special histiocytes - in loose irregular clusters - located in the sinuses, i.e. sinus histiocytosis - key feature:
  • Do not form granuloma; may be similar to toxoplasma.
• Plasma cells (medulla).
• Eosinophils.

Histiocytes & special histiocytes:

• Histiocytes:
  • +/-Melanin pigment key feature (if present).
  • Lipid-laden macrophages.
• Interdigitating dendritic cells:
  • Need IHC to identify definitively.
• Langerhans cells:
  • Classically have a kidney bean nuclei.
  • Need IHC to identify definitively.

DDx:

• Metastatic malignant melanoma - (melanin) pigmented cells have nuclear atypia, not histiocytes.
• Sinus histiocytosis - no cells with melanin.

Images

• 

  DL - very low mag. (WC)

• 

  DL - low mag. (WC)

• 

  DL - intermed. mag. (WC)

• 

  DL - high mag. (WC)

• 

  DL - very high mag. (WC)

IHC

• Interdigitating dendritic cells: S100 +ve, CD1a -ve.
• Langerhans cells: S100 +ve, CD1a +ve.

Kimura lymphadenopathy

Main article: Kimura disease

Microscopic

Features:

• Abundant eosinophils.
• Thick-wall blood vessels.

Rosai-Dorfman disease

• Abbreviated RDD.

General

• AKA sinus histiocytosis with massive lymphadenopathy, abbreviated SHML.
• Super rare.
• Prognosis - good.

Microscopic

Features:

• Sinus histiocytosis:
  • Histiocytes - abundant.
    • Singular large round nuclei ~2x the size of resting lymphocyte.
      • Prominent nucleolus - visible with 10x objective.
    • Abundant cytoplasm.
• Emperipolesis (from Greek: em = inside, peri = around, polemai = wander about):
  • Histiocytes contain other whole cells: neutrophils, lymphocytes, plasma cells.
    • The "eaten" cell is within a vacuole; thus, it should have a clear halo around it.
    • Thought to be related to peripolesis; the attachment of a cell to another.

DDx:

• Other histiocytosis:
  • Langerhans cell histiocytosis.
  • Erdheim-Chester disease.
• Infection, e.g. rhinoscleroma (nasopharynx), xanthogranulomatous pyelonephritis.
• Xanthomatous change.

Images

• 

  Emperipolesis in SHML (WC)

• 

  Rosai-Dorfman disease (WC)

• 

  Rosai-Dorfman disease - S100 showing emperipolesis (WC)

www:

• RDD - case 1 - several images (upmc.edu).
• RDD - case 2 - several images of breast (upmc.edu).
• RDD - case 3 - several images (upmc.edu).
• RDD - case 4 - several images (upmc.edu).

IHC

• CD68 +ve.
• S100 +ve.
  • Useful for seeing emperipolesis.
• CD1a -ve.
  • CD1a positive in Langerhans cell histiocytosis.

Langerhans cell histiocytosis

Main article: Langerhans cell histiocytosis

Microscopic

Features:

• Langerhans cells histiocytes - key feature.
  • Clusters of cells (histiocytes) with a reniform (kidney-shaped) nucleus and abundant foamy cytoplasm.
• +/-Eosinophils - often prominent.

See Langerhans cell histiocytosis for details.

Lymph node hyalinization

• AKA hyalinized lymph node.

General

• Benign.
• Associated with aging.

Microscopic

Features:

• Hyaline material (acellular pink stuff on H&E) within a lymph node.

Subdivided into:

• Mediastinal-type.
  • Usually in medullary sinus.
  • Onion peel-like appearance.
• Pelvic-type hyalinization.
  • Discrete round, eosinophilic, glassy appearance at low power, whirled/fibrous at high power.
  • +/-Calcification.

DDx:

• Amyloidosis - cotton candy-like appearance, usu. no calcifications.

Images:

• Lymph node with amyloidosis - several images (flickriver.com).

See also

• Haematopathology.