Lymph node pathology

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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 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 ?
Metastasis foreign cell population, usu. in subcapsular sinuses +/-nuclear atypia, +/-malignant architecture dependent on tumour type (see IHC) dependent on morphology CRC met, Breast met, PTC met
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 [1], [2]
Toxoplasmosis large follicles; epithelioid cells perifollicular & intrafollicular reactive GCs, monocytoid cell clusters, epithelioid cells IHC for toxoplasma NSRFH, HIV/AIDS, Hodgkin's lymphoma [3], [4]
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 [5]
Cat-scratch disease PMNs in necrotic area "stellate" (or serpentine) shaped microabscesses, granulomas B. henselae, Dieterle stain HIV/AIDS, NSRFH [6]
Dermatopathic lymphadenopathy melanin-laden histiocytes histiocytosis S100+ve (interdigitating dendritic cells), CD1a+ve (Langerhans cells) DDx ? [7], [8]
Kimura disease eosinophils angiolymphoid proliferation (thick-walled blood vessels with hobnail endothelial cells) IHC ? eosinophilic granuloma [9]
Langerhans cell histiocytosis abundant histiocytes with reniform nuclei often prominent eosinophilia S100+, CD1a+ Kimura disease (eosinophilia), Rosai-Dorfman disease [10]
Rosai-Dorfman disease sinus histiocytosis emperipolesis (intact cell within a macrophage) S100+, CD1a- Langerhans cell histiocytosis [11]
Systemic lupus erythematosus lymphadenopathy (blue) hematoxylin bodies necrosis, no PMNs IHC for large cell lymphoma (CD30 + others) Kikuchi disease, large cell lymphomas [12]
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 [13], [14]
Castleman disease, plasma cell variant thick mantle cell layer sinus perserved, interfollicular plasma cells, mitoses in GC HHV-8 HIV/AIDS image ?

Follicular lymphoma vs. reactive follicular hyperplasia

Factors to consider:[1]

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

Metastasis

General

  • Determination of lymph node status is probably the most common indication 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.

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:

  • 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.

Images:

Progressive transformation of germinal centers

Main article: Progressive transformation of germinal centers
  • Abbreviated as PTGC.

General

  • Benign.
  • Classically in younger patients.
  • Associated with nodular lymphocyte predominant Hodgkin's lymphoma (NLPHL); NLPHL found in up to 5% in a 7 year follow-up.[2]

Clinical:

  • Asymptomatic lymphadenopathy.

Microscopic

Features:

  • Follicular hyperplasia (many follicles).
  • Focally large germinal centers with:
    • Poorly demarcated germinal center (GC)/mantle zone interfaces (as GCs infiltrated by mantle zone lymphocytes) -- key feature.[2]
    • Expanded mantle zone.

Images:

Reactive follicular hyperplasia

General

  • Many causes - including: bacteria, viruses, chemicals, drugs, allergens.
    • In only approximately 10% can definitive cause be identified.[3]

Microscopic

Features:[4]

  • 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:[4]

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

Sinus histiocytosis

General

  • Benign.

Microscopic

Features:[4]

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

Notes:

  • Sinus histiocytosis should prompt consideration of Rosai-Dorfman disease.
    • Look for large nuclei (~2x lymphocyte) with prominent nucleoli.

Kikuchi disease

General

  • AKA histiocytic necrotising lymphadenitis (HNL),[5] and Kikuchi-Fujimoto disease.
  • Rare disease that may mimic cancer, esp. lymphoma.
    • May cause fever & systemic symptoms.[6]

Epidemiology:[6]

  • Usually <40 years old.
  • Asian.
  • Female:Male = 3:1.[7]

Treatment:

  • Usually self-limited.[6]
  • Oral corticosteroids.

DDx:

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

Micrograph

Features (the three main features - just as the name suggests):[8]

  • Histiocytes.
    • May be crescentic.
  • Necrosis (due to apoptosis) - paracortical areas.[6]
    • Necrosis without neutrophils - key feature.
  • Lymphocytes (CD8 +ve).
  • Plasmacytoid dendritic cells.

Notes:

  • Dendritic cell - vaguely resembles a macrophage:[9]
    • Long membrane projections - key feature.
    • Abundant blue-grey cytoplasm, +/- ground-glass appearance.
    • Nucleus: small, ovoid, usu. single nucleolus.

Images:

IHC

  • CD68 +ve.
  • CD8 +ve - usu. predominant.
  • CD4, CD20, CD3, and CD30 - mixed.
    • Done to excluded lymphoma; esp. large cell lymphomas;[10] should show a mixed population of lymphocytes.
  • Others:
    • CD56 -ve.

Systemic lupus erythematosus lymphadenopathy

General

  • Lymphadenopathy associated with systemic lupus erythematosus (SLE).

Microscopic

Features:[11]

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

Images:

DDx:

  • Kikuchi disease.

Castleman disease

General

  • AKA angiofollicular lymph node hyperplasia, giant lymph node hyperplasia.[12]
  • Benign.
  • Abbreviated CD.

Classification

CD is grouped by histologic appearance:[13]

  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.[14]
  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.[15]

Microscopic

Hyaline-vascular variant (HVV)

Features:[16][17]

  • 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:

Plasma cell variant

Features:[17]

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

IHC

Hyaline-vascular variant:

Plasma cell variant:

  • HHV-8 +ve.

Cat-scratch disease

General

  • AKA Cat-scratch fever.
  • Infection caused Bartonella henselae,[18] a gram-negative bacilla (0.3-1.0 x 0.6-3.0 micrometers) in chains, clumps, or singular.[19]
  • Treatment: antibiotics.

Clinical

Features:[20]

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

Micrograph

Features:[20]

  • 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.

Stains:

  • Warthin-Starry stain +ve.
  • B. henselae IHC stain +ve.

Images:

Toxoplasma lymphadenitis

Main article: Toxoplasma

General

  • Caused by protozoan Toxoplasma gondii.

Microscopic

Features:[20]

  • 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:

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:[21]

  • 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.

Images:

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.

IHC:

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

Kimura lymphadenopathy

General

  • AKA eosinophilic lymphogranuloma, Kimura disease.
  • Chronic inflammatory disorder - suspected to be infectious.

Clinical:

  • Usually neck, periauricular.
  • Peripheral blood eosinophilia.
  • Increased blood IgE.

Epidemiology

  • Males > females.
  • Young.
  • Asian.

Microscopic

Features:[22]

  • Angiolymphoid proliferation.
    • Thick walled blood vessels with (plump) hobnail endothelial cells.[23]
  • Eosinophils - abundant - key feature.

Notes:

  • Abundant eosinophils: consider Langerhans cell histiocytosis.

Images:

IHC

  • Used to rule-out a clonal population.

Rosai-Dorfman disease

General

  • AKA sinus histiocytosis with massive lymphadenopathy, abbreviated SHML.[24]
  • Super rare.
  • Prognosis - good.

Microscopic

Features:

  • Sinus histiocytosis:
    • Histiocytes - abundant.
      • Singular large round nuclei[25] ~2x the size of resting lymphocyte.
        • Prominent nucleolus - visible with 10x objective.
      • Abundant cytoplasm.
  • Emperipolesis (from Greek: em = inside, peri = around, polemai = wander about[26]):
    • Histiocytes contain other whole cells: neutrophils, lymphocytes, plasma cells.
      • The "eaten" cell is within a vacuole;[27] thus, it should have a clear halo around it.
      • Thought to be related to peripolesis; the attachment of a cell to another.[28]

Images:

DDx:

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

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.

See Langerhans cell histiocytosis for details.

See also

References

  1. ↑ DB. 4 August 2010.
  2. ↑ 2.0 2.1 Verma A, Stock W, Norohna S, Shah R, Bradlow B, Platanias LC (2002). "Progressive transformation of germinal centers. Report of 2 cases and review of the literature". Acta Haematol. 108 (1): 33–8. PMID 12145465.
  3. ↑ Ioachim, Harry L; Medeiros, L. Jeffrey (2008). Ioachim's Lymph Node Pathology (4th ed.). Lippincott Williams & Wilkins. pp. 174. ISBN 978-0781775960.
  4. ↑ 4.0 4.1 4.2 Ioachim, Harry L; Medeiros, L. Jeffrey (2008). Ioachim's Lymph Node Pathology (4th ed.). Lippincott Williams & Wilkins. pp. 179. ISBN 978-0781775960.
  5. ↑ Kaushik V, Malik TH, Bishop PW, Jones PH (June 2004). "Histiocytic necrotising lymphadenitis (Kikuchi's disease): a rare cause of cervical lymphadenopathy". Surgeon 2 (3): 179–82. PMID 15570824.
  6. ↑ 6.0 6.1 6.2 6.3 Hutchinson CB, Wang E (February 2010). "Kikuchi-Fujimoto disease". Arch. Pathol. Lab. Med. 134 (2): 289–93. PMID 20121621.
  7. ↑ URL: http://emedicine.medscape.com/article/210752-overview. Accessed on: 3 June 2010.
  8. ↑ URL: http://www.ispub.com/journal/the_internet_journal_of_head_and_neck_surgery/volume_1_number_1_30/article_printable/kikuchi_s_lymphadenitis_in_a_young_male.html. Accessed on: 1 June 2010.
  9. ↑ URL: http://www.healthsystem.virginia.edu/internet/hematology/hessedd/benignhematologicdisorders/normal-hematopoietic-cells/dendritic-cell.cfm?drid=214. Accessed on: 3 June 2010.
  10. ↑ Good DJ, Gascoyne RD (August 2009). "Atypical lymphoid hyperplasia mimicking lymphoma". Hematol. Oncol. Clin. North Am. 23 (4): 729–45. doi:10.1016/j.hoc.2009.04.005. PMID 19577167.
  11. ↑ Kojima, M.; Nakamura, S.; Itoh, H.; Yoshida, K.; Asano, S.; Yamane, N.; Komatsumoto, S.; Ban, S. et al. (1997). "Systemic lupus erythematosus (SLE) lymphadenopathy presenting with histopathologic features of Castleman' disease: a clinicopathologic study of five cases.". Pathol Res Pract 193 (8): 565-71. PMID 9406250.
  12. ↑ URL: http://www.mayoclinic.com/health/castleman-disease/DS01000. Accessed on: 17 June 2010.
  13. ↑ Ioachim, Harry L; Medeiros, L. Jeffrey (2008). Ioachim's Lymph Node Pathology (4th ed.). Lippincott Williams & Wilkins. pp. 228. ISBN 978-0781775960.
  14. ↑ Humphrey, Peter A; Dehner, Louis P; Pfeifer, John D (2008). The Washington Manual of Surgical Pathology (1st ed.). Lippincott Williams & Wilkins. pp. 596. ISBN 978-0781765275.
  15. ↑ Cronin, DM.; Warnke, RA. (Jul 2009). "Castleman disease: an update on classification and the spectrum of associated lesions.". Adv Anat Pathol 16 (4): 236-46. doi:10.1097/PAP.0b013e3181a9d4d3. PMID 19546611.
  16. ↑ URL: http://www.ispub.com/journal/the_internet_journal_of_otorhinolaryngology/volume_9_number_2_11/article/a_rare_case_of_castleman_s_disease_presenting_as_cervical_neck_mass.html. Accessed on: 15 June 2010.
  17. ↑ 17.0 17.1 Ioachim, Harry L; Medeiros, L. Jeffrey (2008). Ioachim's Lymph Node Pathology (4th ed.). Lippincott Williams & Wilkins. pp. 236. ISBN 978-0781775960.
  18. ↑ Jerris, RC.; Regnery, RL. (1996). "Will the real agent of cat-scratch disease please stand up?". Annu Rev Microbiol 50: 707-25. doi:10.1146/annurev.micro.50.1.707. PMID 8905096.
  19. ↑ Ioachim, Harry L; Medeiros, L. Jeffrey (2008). Ioachim's Lymph Node Pathology (4th ed.). Lippincott Williams & Wilkins. pp. 110. ISBN 978-0781775960.
  20. ↑ 20.0 20.1 20.2 Ioachim, Harry L; Medeiros, L. Jeffrey (2008). Ioachim's Lymph Node Pathology (4th ed.). Lippincott Williams & Wilkins. pp. 113. ISBN 978-0781775960.
  21. ↑ Ioachim, Harry L; Medeiros, L. Jeffrey (2008). Ioachim's Lymph Node Pathology (4th ed.). Lippincott Williams & Wilkins. pp. 226. ISBN 978-0781775960.
  22. ↑ Ioachim, Harry L; Medeiros, L. Jeffrey (2008). Ioachim's Lymph Node Pathology (4th ed.). Lippincott Williams & Wilkins. pp. 190. ISBN 978-0781775960.
  23. ↑ URL: http://emedicine.medscape.com/article/1098777-diagnosis. Accessed on: 8 August 2010.
  24. ↑ Agarwal A, Pathak S, Gujral S (October 2006). "Sinus histiocytosis with massive lymphadenopathy--a review of seven cases". Indian J Pathol Microbiol 49 (4): 509–15. PMID 17183839.
  25. ↑ DB. 24 August 2010.
  26. ↑ Stedman's Medical Dictionary. 27th Ed.
  27. ↑ Viswanathan P, Raghunathan K, Majhi U, Pandit RV, Shanthi R, Rajkumar T (1997). Emperipolesis : an electron microscopic characteristic in RDD (Rosai-Dorfaman disease) : a case report. pp. 14-6. http://www.ijmpo.org/article.asp?issn=0971-5851;year=1997;volume=18;issue=1;spage=14;epage=16;aulast=Viswanathan;type=0.
  28. ↑ Lyons DJ, Gautam A, Clark J, et al. (January 1992). "Lymphocyte macrophage interactions: peripolesis of human alveolar macrophages". Eur. Respir. J. 5 (1): 59–66. PMID 1577151.
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