Lymph nodes & spleen, nonlymphoma

Lymph node-nonspecific findings

Granulomatous inflammation


Editorial Board Member: Elizabeth Courville, M.D.
Deputy Editor-in-Chief: Patricia Tsang, M.D., M.B.A.
Simon A. Backer, M.D.
Sumire Kitahara, M.D.

Last author update: 5 January 2023
Last staff update: 5 January 2023

Copyright: 2003-2023, PathologyOutlines.com, Inc.

PubMed Search: Granulomatous inflammation

Simon A. Backer, M.D.
Sumire Kitahara, M.D.
Page views in 2022: 7,723
Page views in 2023 to date: 1,172
Cite this page: Backer SA, Kitahara S. Granulomatous inflammation. PathologyOutlines.com website. https://www.pathologyoutlines.com/topic/lymphnodesgranulomatous.html. Accessed February 6th, 2023.
Definition / general
  • Specialized immune response against various inflammatory insults, involving chronic activation and organization of mononuclear phagocytic cells (macrophages) (J Clin Tuberc Other Mycobact Dis 2017;7:1)
  • Histologically characterized by epithelioid histiocytes, with or without central necrosis, surrounded by acute or chronic inflammation
Essential features
  • Specialized inflammatory response against various offending entities, including (StatPearls: Granuloma [Accessed 13 June 2022]):
    • Infectious (usually necrotic, suppurative)
    • Autoimmune / inflammatory
    • Malignancy
    • Others (see below)
  • Histologically characterized by central epithelioid histiocytes surrounded by acute or chronic inflammation
  • Microbiologic cultures of fresh sample, special stains / immunohistochemistry for microorganisms are essential when clinical history includes suspicion of infection or an immunocompromised / suppressed state
  • Immunohistochemistry to evaluate for malignancies that arise as differential diagnoses (e.g., carcinoma [cytokeratin], melanoma [SOX10]) (O'Malley: Benign and Reactive Conditions of Lymph Node and Spleen, 1st Edition, 2009)
Terminology
  • Lymphadenitis (LA), infectious lymphadenitis, granulomatous lymphadenitis (GLA)
ICD coding
  • ICD-10:
    • I88.1 - chronic or subacute lymphadenitis
    • I88.8 - granuloma, gland (lymph)
    • I88.9 - lymphadenitis
    • L04.9 - acute lymphadenitis
    • D86.1 - sarcoidosis of lymph nodes
Epidemiology
Sites
Pathophysiology
  • Dysregulation of immune response due to inability of macrophages to clear the offending agent (StatPearls: Granuloma [Accessed 13 June 2022])
  • Results in chronic active inflammation, histologically characterized by (StatPearls: Granuloma [Accessed 13 June 2022]):
    • Central collection of epithelioid histiocytes
    • Rim of plasma cells and lymphocytes
    • Central necrosis or suppuration, depending on etiology
  • Can be conceptualized as consisting of 3 phases (J Clin Exp Hematop 2012;52:1):
    • Initiation / accumulation, peak and late phase
    • Initiation characterized by activation of T cells via MHC class II interactions with antigen presenting cells (APCs) (J Clin Tuberc Other Mycobact Dis 2017;7:1)
      • Activated T helper 1 (Th1) cells stimulate and recruit macrophages via secretion of TNF alpha, IFN gamma, IL2, IL12 and chemokines
    • Precise mechanism of defective downregulation of active inflammation is poorly understood
    • With ensuing active inflammation, peak phase is characterized by rim of chronic inflammatory infiltrate consisting of:
      • CD4+ T cells, CD8+ T cells, NK cells, plasma cells and occasional granulocytes
      • Certain infectious GLA features prominent monocytoid B cell infiltrates (Toxoplasma lymphadenitis, Bartonella) (J Clin Exp Hematop 2012;52:1)
        • Role poorly understood
    • Late phase characterized by fibrosis and hyalinization
  • Resolution occurs after clearance of antigenic stimulus and is characterized by a fibrous scar
Etiology
  • Infectious:
    • Suppurative (purulent):
      • Tularemia lymphadenitis (Francisella tularensis)
      • Cat scratch lymphadenitis (Bartonella henselae)
      • Yersinia lymphadenitis (Yersinia enterocolitica)
      • Various fungal infections
    • Nonsuppurative:
      • Tuberculous lymphadenitis (Mycobacterium tuberculosis spp.)
      • Atypical mycobacterial infection
      • Bacillus Calmette-Guérin (BCG) lymphadenitis
      • Toxoplasma lymphadenitis
      • Hansen disease or leprosy (M. leprae)
      • Syphilis
      • Brucellosis
      • Fungal lymphadenitis (Coccidioides, Cryptococcus, Histoplasma, Pneumocystis)
  • Noninfectious:
    • Systemic sarcoidosis
    • Foreign body (berylliosis, silicosis)
    • Malignancies (lymphoma, carcinoma, especially breast, uterus, lung, stomach)
    • Systemic inflammatory / autoimmune conditions (lupus [SLE], rheumatoid arthritis [RA], granulomatosis with polyangiitis [GPA])
    • Toxic (chemotherapy, heavy metals, beryllium, zirconium, silicon)
    • Histiocytic inflammatory (Rosai-Dorfman disease, Castleman disease)
  • Reference: J Clin Tuberc Other Mycobact Dis 2017;7:1
Clinical features
Diagnosis
  • Clinical exam
  • Imaging:
    • CT
    • Ultrasound
  • Tissue biopsy:
    • Excisional preferred over needle core biopsies, due to preservation of lymph node architecture; usually yields sufficient tissue to perform ancillary studies (microbiologic studies, special stains, immunostains)
  • Fine needle aspiration (FNA):
    • Can be ultrasound guided
  • Reference: StatPearls: Lymphadenopathy [Accessed 13 June 2022]
Laboratory
  • Dependent on suspected etiology but generally includes:
    • Microbiologic studies (e.g., cultures, serology)
      • Essential to obtain tissue cultures, as necrotic node usually contains high density of organisms
    • Autoimmune / rheumatology workup
    Reference: StatPearls: Lymphadenopathy [Accessed 13 June 2022]
Prognostic factors
  • Dependent on etiology (e.g., HIV, sarcoidosis, malignancy, infection)
Case reports
Treatment
  • Management of underlying disease (e.g., infection, neoplasm, inflammatory / autoimmune)
  • Removal of offending agent (e.g., removal of foreign body)
Gross description
  • Pale tan circumscribed nodules
  • Fibrotic and firm compared to surrounding lymph node parenchyma
  • Can show central necrosis, which can be dry and crumbly (caseating) or soft with a gelatinous consistency
  • Can show gross suppuration
  • Reference: Foucar: Tumors of the Bone Marrow, 1st Edition, 2016
Gross images

Contributed by Ryan Hickey, PA (ASCP)
Inguinal lymph node with necrotizing granuloma

Inguinal lymph node with necrotizing granuloma

Frozen section description
Microscopic (histologic) description
  • Collection of epithelioid macrophages with abundant eosinophilic cytoplasm and indistinct cell borders (StatPearls: Granuloma [Accessed 13 June 2022])
  • Surrounded by a rim of inflammatory cells, including lymphocytes, plasma cells and macrophages (StatPearls: Granuloma [Accessed 13 June 2022])
  • Multinucleated giant cells are often present (StatPearls: Granuloma [Accessed 13 June 2022])
  • Certain etiologies may demonstrate characteristic features
    • May present as a characteristic triad of florid follicular hyperplasia, interfollicular monocytoid B cells and cortical / subcortical, ill defined aggregates of epithelioid cells (Toxoplasma lymphadenitis)
  • Subtypes:
    • Necrotizing granulomas (J Clin Exp Hematop 2012;52:1):
      • Necrotic focus surrounded by a rim of chronic inflammatory cells, including epithelioid macrophages
      • May show suppuration (acute inflammation) depending on etiology
      • Usually associated with infectious agents (e.g., tuberculosis, lymphogranuloma venereum, tularemia, cat scratch disease, fungal)
        • Important to look for organisms within granulomas
        • Use special stains to highlight
        • Often essential for diagnosis as serology may have low sensitivity / specificity
        • Obtain tissue culture
    • Nonnecrotizing (sarcoid and sarcoid-like) granulomas (J Clin Exp Hematop 2012;52:1):
      • Well defined borders, cohesive solid appearance, no central necrosis
      • Various types of inclusions inside macrophages (e.g., asteroid bodies)
      • Etiology includes
        • Sarcoidosis containing Langhans type giant cells containing nuclei arranged in a horseshoe shape along cell periphery
        • Systemic / autoimmune entities
        • Foreign body type lymphadenitis containing giant cells with haphazardly arranged nuclei and engulfed foreign material
      • Lipogranuloma (O'Malley: Benign and Reactive Conditions of Lymph Node and Spleen, 1st Edition, 2009):
        • Frequently found in spleen; can be seen in lymph node
        • Focus of macrophages with ingested fat surrounded by a rim of lymphocytes and plasma cells
        • Etiology is unknown
        • Has been associated with excessive topical application / ingestion of mineral oils
Microscopic (histologic) images

Contributed by Simon A. Backer, M.D.
Necrotizing granuloma in a cervical lymph node

Necrotizing granuloma in a cervical lymph node

Infectious (suppurative) granulomatous lymphadenitis

Infectious (suppurative) granulomatous lymphadenitis

Sarcoid granuloma

Sarcoid granuloma

Sarcoid granuloma with asteroid body

Sarcoid granuloma with asteroid body

Necrotizing granuloma with palisading histiocytes

Necrotizing granuloma with palisading histiocytes

GMS with fungal forms in necrotizing granuloma

GMS with fungal forms in necrotizing granuloma

Cytology description
  • Sarcoid granulomatous lymphadenitis:
    • Tight collection of epithelioid histiocytes in syncytial arrangement with curved nuclei in horseshoe, C or V shape
  • Infectious type granulomatous lymphadenitis:
    • Histiocyte cluster may be loose or tight
    • Usually surrounded by abundant acute inflammation
    • Can show suppuration or necrosis, depending on infectious etiology
  • Ultimately, findings are nonspecific and microbiologic, serologic studies are needed for a definitive etiology
  • Reference: Cibas: Cytology - Diagnostic Principles and Clinical Correlates, 5th Edition, 2020
Cytology images

Contributed by Simon A. Backer, M.D.
Epithelioid granuloma

Epithelioid granuloma

Positive stains
  • CD68, CD163, lysozyme: highlights epithelioid histiocytes
  • CD3, CD20: highlights immunoarchitecture; rules out lymphoma
Negative stains
Sample pathology report
  • R4 lymph node, excision:
    • Nonnecrotizing granulomatous lymphadenitis (see comment)
    • No evidence of malignancy identified
    • Comment: The overall findings raise the possibility of sarcoidosis; infection remains in the differential diagnosis. AFB and GMS stains are negative for acid fast organisms and fungal forms. Clinical correlation with microbiologic studies is recommended.
Differential diagnosis
Board review style question #1

A 30 year old pregnant woman presents to her general practitioner complaining of mild flu-like symptoms. On physical examination, there is small but palpable, tender cervical lymphadenopathy. She states that her allergies seem to be acting up lately, which may be due to her new cat. She reports a family history of lymphoma in a grandparent and would like the lymph node biopsied. Sections of the node reveal secondary follicles of varying shapes and sizes, clusters of monocytoid lymphoid cells and cortical, loose collections of epithelioid histiocytes. Based on the clinical presentation and histologic findings, what is the most likely etiology for this patient's presentation?

  1. Cat scratch disease
  2. Follicular lymphoma
  3. Metastatic carcinoma
  4. Toxoplasmosis
  5. Tularemia
Board review style answer #1
D. Toxoplasmosis

Comment Here

Reference: Granulomatous inflammation
Board review style question #2
You receive an excisional biopsy of an enlarged superficial neck lymph node from a 55 year old homeless man who was found obtunded. He is a poor historian and is unable to provide the duration of the adenopathy but he reports feeling unwell for quite some time. On physical examination, he has somewhat tender cervical adenopathy, as well as axillary and inguinal adenopathy. In addition, imaging studies show mediastinal and intra-abdominal adenopathy. Biopsy sections of the superficial cervical node show follicular hyperplasia with scattered epithelioid granulomas that are nonnecrotizing. The expanded follicles show a monotonous proliferation of small to medium lymphocytes, with variably irregular nuclear contours, condensed chromatin and scant cytoplasm. Occasional larger lymphoid cells are seen. Interfollicular plasma cells, eosinophils and scattered epithelioid histiocytes are also seen. What additional studies could narrow your differential diagnosis?

  1. AFB and GMS stains
  2. Immunostains to evaluate for both non-Hodgkin and Hodgkin lymphomas
  3. PCR studies for HIV
  4. Serologic studies for infectious etiologies
  5. Tissue culture of fresh tissue sent to the microbiology laboratory
Board review style answer #2
B. Immunostains to evaluate for both non-Hodgkin and Hodgkin lymphomas

Comment Here

Reference: Granulomatous inflammation
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