Stains & CD markers
CD68


Last author update: 16 May 2022
Last staff update: 5 July 2022

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PubMed Search: CD68

Frido Bruehl, M.D.
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Cite this page: Caraccio C, Bruehl F. CD68. PathologyOutlines.com website. https://www.pathologyoutlines.com/topic/cdmarkerscd68.html. Accessed August 11th, 2022.
Definition / general
  • Lysosomal associated transmembrane glycoprotein that is present in a variety of normal and neoplastic cell types and is primarily used as a marker to identify histiocytes and histiocytic tumors
Essential features
  • Lysosomal marker used to identify histiocytic and monocytic cells with limited specificity
  • KP1 and PGM1 are the 2 most commonly used antibody clones, with PGM1 being the slightly more specific marker
Terminology
  • Lysosomal associated membrane protein 4 (LAMP4)
  • Gp110
  • Scavenger receptor class D member 1 (SCARD1)
  • Macrosilian (murine analog)
  • KP1 (common antibody clone)
  • PGM1 (common antibody clone)
  • EBM11 (less commonly used antibody clone)
  • KiM6 and KiM7 (less commonly used antibody clones)
Pathophysiology
Interpretation
Uses by pathologists
  • Histiocytic malignancies are usually CD68 positive (Am J Clin Pathol 2004;122:794)
  • CD68 is used to diagnose histiocytic sarcoma, which usually expresses at least 2 of the following markers: CD68, CD163, CD4, lysozyme (Blood 2016;127:2672)
  • Myeloid / monocytic sarcoma is usually CD68 positive (Leukemia 2007;21:340)
  • PGM1 is more specific to monocyte / macrophages than KP1, which is widely reactive (Ann Rheum Dis 2004;63:774)
  • Renal cell carcinoma with t(6;11) is consistently KP1 positive and PGM1 negative, whereas epithelioid angiomyolipoma is KP1 and PGM1 positive (Mod Pathol 2018;31:474)
  • Double staining of CD68 and CD31 can aid in the diagnosis of antibody mediated rejection by labeling intracapillary macrophages (Am J Transplant 2019;19:3149)
  • CD68 can aid in identification of chronic granulomatous disease (CGD) in patients with colonic inflammation; CGD patients have a significantly smaller average of CD68 positive cells per mm2 of lamina propria (242.3 cells/mm2) than patients with Crohn’s disease (1,104.2 cells/mm2) and the control group (565.4 cells/mm2) (Inflamm Bowel Dis 2009;15:1213)
  • CD68 can aid in the differential diagnosis between cellular fibrous histiocytoma (83% KP1 positive) and dermatofibrosarcoma protuberans (6% KP1 positive) (J Cutan Pathol 2006;33:353)
  • Primary cutaneous acral CD8 positive T cell lymphoproliferative disorder shows dot-like CD68 positivity, allowing it to be distinguished from other primary or secondary cutaneous CD8 positive T cell lymphomas (Br J Dermatol 2015;172:1573)
Prognostic factors
  • Elevated numbers of CD68 positive tumor associated macrophages (TAMs) correlate with negative survival outcomes in many cancer types; TAMs are predominantly M2 macrophages, which can promote tumor growth / spread through the secretion of MMP9, VEGF, EGF and TGF1 (Clin Transl Oncol 2016;18:251)
    • Anaplastic large cell lymphoma (ALCL): increased intratumoral TAMs correlate with an adverse outcome in anaplastic lymphoma kinase negative ALCL (Histopathology 2014;65:490)
    • Breast cancer: increased TAMs predict worse cancer specific survival and a shorter disease free interval; patients with lower TAM levels showed improved metastasis free survival (J Clin Pathol 2012;65:159, Int J Cancer 2012;131:426)
    • Diffuse large B cell lymphoma: TAMs are associated with a favorable prognosis when patients are treated with rituximab in addition to multiagent chemotherapy and with a poor outcome when rituximab is not given (Haematologica 2015;100:143)
    • Classical Hodgkin lymphoma: studies have suggested elevated TAM expression as a negative indicator of survival in classical Hodgkin lymphoma; however, this association has been disputed (Leuk Lymphoma 2011;52:1913, N Engl J Med 2010;362:875, Diagn Pathol 2020;15:10, BMC Med 2016;14:159, Ann Oncol 2012;23:736)
    • Follicular lymphoma: TAMs are associated with adverse outcomes in chemotherapy treated patients; in contrast, after a rituximab and chemotherapy combination regimen, high TAM content is correlated with longer overall survival (Clin Cancer Res 2007;13:5784)
    • Hepatocellular carcinoma: density of peritumoral TAMs is associated with poor recurrence free survival and poor overall survival (PLoS One 2013;8:e59771)
    • Squamous cell carcinoma of the head and neck: increased TAMs are associated with worse relapse free survival, worse disease specific survival and worse overall survival (Head Neck 2016;38:1074, Oral Oncol 2015;51:90)
    • Myxoid liposarcoma: increased TAMs are associated with poorer overall survival rate (Br J Cancer 2015;112:547)
    • Urothelial carcinoma: a high CD68/CD3 positive ratio identifies a bad prognosis group among muscle invasive cases (Urol Oncol 2014;32:791)
    • Brain tumors: CD68 TAMs are associated with higher tumor grade in astrocytoma (Clin Cancer Res 2013;19:3776)
Microscopic (histologic) images

Contributed by Frido Bruehl, M.D.
Fibrolamellar carcinoma of the liver, H&E Fibrolamellar carcinoma of the liver, CD68

Fibrolamellar carcinoma of the liver

Kikuchi-Fujimoto disease of the lymph node, H&E Kikuchi-Fujimoto disease of the lymph node, CD68

Kikuchi-Fujimoto disease of the lymph node

Reticulohistiocytoma of the skin, H&E Reticulohistiocytoma of the skin, CD68

Reticulohistiocytoma of the skin

Virtual slides

Images hosted on other servers:

CD68+ histiocytes in Kikuchi-Fujimoto lymphadenitis

CD68+ histiocytic origin of juvenile xanthogranuloma

CD68+ systemic mastocytosis, small intestine

Positive staining - normal
Positive staining - disease
Negative staining
Sample pathology report
  • Skin, biopsy:
    • Diagnosis: myeloid / monocytic sarcoma (see comment)
    • Comment: The skin biopsy shows a dense infiltrate of intermediate sized cells with open and dispersed chromatin, irregular nuclear contours, variable amounts of cytoplasm and frequent mitotic figures. Areas of tumoral necrosis are present. Immunohistochemical stains show that the atypical infiltrate are positive for CD4, CD33, CD43, CD68 (KP1) and CD68 (PGM1). The atypical cells are negative for CD3, CD20, PAX 5, CD34, CD56, CD123 and muramidase. A Ki67 stain is positive in 90% of tumor cell nuclei. In summary, these findings represent involvement by myeloid / monocytic sarcoma.
Board review style question #1

Which of the following marker combinations fits the immunoprofile of Langerhans cell histiocytosis (LCH)?

  1. CD68 negative, CD1a negative, CD207 (langerin) negative
  2. CD68 negative, CD1a positive, CD207 (langerin) positive
  3. CD68 positive, CD1a negative, CD207 (langerin) negative
  4. CD68 positive, CD1a positive, CD207 (langerin) positive
Board review style answer #1
D. CD68 positive, CD1a positive, CD207 (langerin) positive. LCH cells are positive for CD68, a traditional histiocyte marker, as well as CD1a and CD207 (langerin), typical Langerhans cell markers. CD1a and CD207 positivity (as opposed to answer choice C) can distinguish surrounding CD68 positive macrophages from LCH cells.

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Reference: CD68
Board review style question #2

CD68 IHC can be helpful in which of the following differential diagnostic scenarios?

  1. Chronic granulomatous disease versus Whipple disease
  2. Clear cell renal cell carcinoma versus chromophobe renal cell carcinoma
  3. Reticulohistiocytoma versus neurothekeoma
  4. Rhabdomyoma versus granular cell tumor
  5. Rheumatoid nodules versus granuloma annulare
Board review style answer #2
D. Rhabdomyoma versus granular cell tumor. Granular cell tumors are diffusely CD68 positive whereas rhabdomyomas are CD68 negative. Chronic granulomatous disease and Whipple disease are both marked by an abundance of CD68 positive macrophages in the lamina propria (A). Clear cell renal cell carcinoma and chromophobe renal cell carcinoma are CD68 negative (B). Reticulohistiocytoma is uniformly CD68 positive, while (cellular) neurothekeoma may be positive in over half of cases (C). Rheumatoid nodules and granuloma annulare both contain many CD68 positive macrophages (E).

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Reference: CD68
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